TY  - JOUR
AU  - Sieghart, Werner
AU  - Chiou, Lih-Chu
AU  - Ernst, Margot
AU  - Fabjan, Jure
AU  - Savić, Miroslav
AU  - Lee, Ming Tatt
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4107
AB  - GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors.
PB  - American Society for Pharmacology and Experimental Therapy
T2  - Pharmacological Reviews
T1  - α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials
VL  - 74
IS  - 1
SP  - 238
EP  - 270
DO  - 10.1124/PHARMREV.121.000293
ER  - 

@article{
author = "Sieghart, Werner and Chiou, Lih-Chu and Ernst, Margot and Fabjan, Jure and Savić, Miroslav and Lee, Ming Tatt",
year = "2022",
abstract = "GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors.",
publisher = "American Society for Pharmacology and Experimental Therapy",
journal = "Pharmacological Reviews",
title = "α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials",
volume = "74",
number = "1",
pages = "238-270",
doi = "10.1124/PHARMREV.121.000293"
}

Sieghart, W., Chiou, L., Ernst, M., Fabjan, J., Savić, M.,& Lee, M. T.. (2022). α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials. in Pharmacological Reviews
American Society for Pharmacology and Experimental Therapy., 74(1), 238-270.
https://doi.org/10.1124/PHARMREV.121.000293

Sieghart W, Chiou L, Ernst M, Fabjan J, Savić M, Lee MT. α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials. in Pharmacological Reviews. 2022;74(1):238-270.
doi:10.1124/PHARMREV.121.000293 .

Sieghart, Werner, Chiou, Lih-Chu, Ernst, Margot, Fabjan, Jure, Savić, Miroslav, Lee, Ming Tatt, "α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials" in Pharmacological Reviews, 74, no. 1 (2022):238-270,
https://doi.org/10.1124/PHARMREV.121.000293 . .

TY  - JOUR
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Knutson, Daniel
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Obradović, Aleksandar
AU  - Fabjan, Jure
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3315
AB  - gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.
PB  - Wiley, Hoboken
T2  - European Journal of Pain
T1  - Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors
VL  - 23
IS  - 5
SP  - 973
EP  - 984
DO  - 10.1002/ejp.1365
ER  - 

@article{
author = "Vasović, Dina and Divović, Branka and Treven, Marco and Knutson, Daniel and Steudle, Friederike and Scholze, Petra and Obradović, Aleksandar and Fabjan, Jure and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2019",
abstract = "gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.",
publisher = "Wiley, Hoboken",
journal = "European Journal of Pain",
title = "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors",
volume = "23",
number = "5",
pages = "973-984",
doi = "10.1002/ejp.1365"
}

Vasović, D., Divović, B., Treven, M., Knutson, D., Steudle, F., Scholze, P., Obradović, A., Fabjan, J., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2019). Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain
Wiley, Hoboken., 23(5), 973-984.
https://doi.org/10.1002/ejp.1365

Vasović D, Divović B, Treven M, Knutson D, Steudle F, Scholze P, Obradović A, Fabjan J, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain. 2019;23(5):973-984.
doi:10.1002/ejp.1365 .

Vasović, Dina, Divović, Branka, Treven, Marco, Knutson, Daniel, Steudle, Friederike, Scholze, Petra, Obradović, Aleksandar, Fabjan, Jure, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors" in European Journal of Pain, 23, no. 5 (2019):973-984,
https://doi.org/10.1002/ejp.1365 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Stephen, Michael
AU  - Verma, Ranjit
AU  - Witzigmann, Christopher
AU  - Meirelles, Matheus
AU  - Zahn, Nicolas
AU  - Huber, Alec
AU  - Arnold, Leggy
AU  - Savić, Miroslav
AU  - Ernst, Margot
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3234
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability
VL  - 255
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3234
ER  - 

@conference{
author = "Knutson, Daniel and Kodali, Revathi and Stephen, Michael and Verma, Ranjit and Witzigmann, Christopher and Meirelles, Matheus and Zahn, Nicolas and Huber, Alec and Arnold, Leggy and Savić, Miroslav and Ernst, Margot and Sieghart, Werner and Cook, James M.",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability",
volume = "255",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3234"
}

Knutson, D., Kodali, R., Stephen, M., Verma, R., Witzigmann, C., Meirelles, M., Zahn, N., Huber, A., Arnold, L., Savić, M., Ernst, M., Sieghart, W.,& Cook, J. M.. (2018). Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 255.
https://hdl.handle.net/21.15107/rcub_farfar_3234

Knutson D, Kodali R, Stephen M, Verma R, Witzigmann C, Meirelles M, Zahn N, Huber A, Arnold L, Savić M, Ernst M, Sieghart W, Cook JM. Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society. 2018;255.
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

Knutson, Daniel, Kodali, Revathi, Stephen, Michael, Verma, Ranjit, Witzigmann, Christopher, Meirelles, Matheus, Zahn, Nicolas, Huber, Alec, Arnold, Leggy, Savić, Miroslav, Ernst, Margot, Sieghart, Werner, Cook, James M., "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability" in Abstracts of Papers of the American Chemical Society, 255 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

TY  - JOUR
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Stephen, Michael
AU  - Zahn, Nicolas
AU  - Dobričić, Vladimir
AU  - Huber, Alec
AU  - Meirelles, Matheus
AU  - Verma, Ranjit
AU  - Wimmer, Laurin
AU  - Witzigmann, Christopher
AU  - Arnold, Leggy
AU  - Chiou, Lih-Chu
AU  - Ernst, Margot
AU  - Mihovilović, Marko D.
AU  - Savić, Miroslav
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3147
AB  - Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.
PB  - Amer Chemical Soc, Washington
T2  - Journal of Medicinal Chemistry
T1  - Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
VL  - 61
IS  - 6
SP  - 2422
EP  - 2446
DO  - 10.1021/acs.jmedchem.7b01664
ER  - 

@article{
author = "Knutson, Daniel and Kodali, Revathi and Divović, Branka and Treven, Marco and Stephen, Michael and Zahn, Nicolas and Dobričić, Vladimir and Huber, Alec and Meirelles, Matheus and Verma, Ranjit and Wimmer, Laurin and Witzigmann, Christopher and Arnold, Leggy and Chiou, Lih-Chu and Ernst, Margot and Mihovilović, Marko D. and Savić, Miroslav and Sieghart, Werner and Cook, James M.",
year = "2018",
abstract = "Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.",
publisher = "Amer Chemical Soc, Washington",
journal = "Journal of Medicinal Chemistry",
title = "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability",
volume = "61",
number = "6",
pages = "2422-2446",
doi = "10.1021/acs.jmedchem.7b01664"
}

Knutson, D., Kodali, R., Divović, B., Treven, M., Stephen, M., Zahn, N., Dobričić, V., Huber, A., Meirelles, M., Verma, R., Wimmer, L., Witzigmann, C., Arnold, L., Chiou, L., Ernst, M., Mihovilović, M. D., Savić, M., Sieghart, W.,& Cook, J. M.. (2018). Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry
Amer Chemical Soc, Washington., 61(6), 2422-2446.
https://doi.org/10.1021/acs.jmedchem.7b01664

Knutson D, Kodali R, Divović B, Treven M, Stephen M, Zahn N, Dobričić V, Huber A, Meirelles M, Verma R, Wimmer L, Witzigmann C, Arnold L, Chiou L, Ernst M, Mihovilović MD, Savić M, Sieghart W, Cook JM. Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry. 2018;61(6):2422-2446.
doi:10.1021/acs.jmedchem.7b01664 .

Knutson, Daniel, Kodali, Revathi, Divović, Branka, Treven, Marco, Stephen, Michael, Zahn, Nicolas, Dobričić, Vladimir, Huber, Alec, Meirelles, Matheus, Verma, Ranjit, Wimmer, Laurin, Witzigmann, Christopher, Arnold, Leggy, Chiou, Lih-Chu, Ernst, Margot, Mihovilović, Marko D., Savić, Miroslav, Sieghart, Werner, Cook, James M., "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability" in Journal of Medicinal Chemistry, 61, no. 6 (2018):2422-2446,
https://doi.org/10.1021/acs.jmedchem.7b01664 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3052
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands
VL  - 256
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3052
ER  - 

@conference{
author = "Knutson, Daniel and Vasović, Dina and Divović, Branka and Treven, Marco and Steudle, Friederike and Scholze, Petra and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands",
volume = "256",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3052"
}

Knutson, D., Vasović, D., Divović, B., Treven, M., Steudle, F., Scholze, P., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 256.
https://hdl.handle.net/21.15107/rcub_farfar_3052

Knutson D, Vasović D, Divović B, Treven M, Steudle F, Scholze P, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society. 2018;256.
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

Knutson, Daniel, Vasović, Dina, Divović, Branka, Treven, Marco, Steudle, Friederike, Scholze, Petra, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands" in Abstracts of Papers of the American Chemical Society, 256 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

TY  - JOUR
AU  - Sieghart, Werner
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3087
AB  - GABAA receptors are themajor inhibitory transmitter receptors in the brain. They are ligand-gated chloride channels and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. GABAA receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 homologous subunits and their distinct regional, cellular, and subcellular distribution gives rise to a large number of GABAA receptor subtypes with distinct pharmacology, which modulate different functions of the brain. A variety of compounds have been identified that were claimed to modulate selectively individual GABAA receptor subtypes. However, many of these compounds have only incompletely been investigated or, in addition to a preferential modulation of a receptor subtype, also modulate other subtypes at similar concentrations. Although their differential efficacy at distinct receptor subtypes reduced side effects in behavioral experiments in rodents, the exact receptor subtypes mediating their behavioral effects cannot be unequivocally delineated. In addition, the discrepant in vivo effects of some of these compounds in rodents and man raised doubts on the applicability of the concept of receptor subtype selectivity as a guide for the development of clinically useful drugs. Here, we provide an up-to-date review on the currently available GABAA receptor subtype-selective ligands. We present data on their actual activity atGABAA receptor subtypes, discuss the translational aspect of subtype-selective drugs, and make proposals for the future development of ligands with better anxioselectivity in humans. Finally, we discuss possible ways to strengthen the conclusions of behavioral studies with the currently available drugs.
PB  - Amer Soc Pharmacology Experimental Therapeutics, Bethesda
T2  - Pharmacological Reviews
T1  - International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
VL  - 70
IS  - 4
SP  - 836
EP  - 878
DO  - 10.1124/pr.117.014449
ER  - 

@article{
author = "Sieghart, Werner and Savić, Miroslav",
year = "2018",
abstract = "GABAA receptors are themajor inhibitory transmitter receptors in the brain. They are ligand-gated chloride channels and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. GABAA receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 homologous subunits and their distinct regional, cellular, and subcellular distribution gives rise to a large number of GABAA receptor subtypes with distinct pharmacology, which modulate different functions of the brain. A variety of compounds have been identified that were claimed to modulate selectively individual GABAA receptor subtypes. However, many of these compounds have only incompletely been investigated or, in addition to a preferential modulation of a receptor subtype, also modulate other subtypes at similar concentrations. Although their differential efficacy at distinct receptor subtypes reduced side effects in behavioral experiments in rodents, the exact receptor subtypes mediating their behavioral effects cannot be unequivocally delineated. In addition, the discrepant in vivo effects of some of these compounds in rodents and man raised doubts on the applicability of the concept of receptor subtype selectivity as a guide for the development of clinically useful drugs. Here, we provide an up-to-date review on the currently available GABAA receptor subtype-selective ligands. We present data on their actual activity atGABAA receptor subtypes, discuss the translational aspect of subtype-selective drugs, and make proposals for the future development of ligands with better anxioselectivity in humans. Finally, we discuss possible ways to strengthen the conclusions of behavioral studies with the currently available drugs.",
publisher = "Amer Soc Pharmacology Experimental Therapeutics, Bethesda",
journal = "Pharmacological Reviews",
title = "International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans",
volume = "70",
number = "4",
pages = "836-878",
doi = "10.1124/pr.117.014449"
}

Sieghart, W.,& Savić, M.. (2018). International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans. in Pharmacological Reviews
Amer Soc Pharmacology Experimental Therapeutics, Bethesda., 70(4), 836-878.
https://doi.org/10.1124/pr.117.014449

Sieghart W, Savić M. International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans. in Pharmacological Reviews. 2018;70(4):836-878.
doi:10.1124/pr.117.014449 .

Sieghart, Werner, Savić, Miroslav, "International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans" in Pharmacological Reviews, 70, no. 4 (2018):836-878,
https://doi.org/10.1124/pr.117.014449 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Verma, Ranjit
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Arnold, Leggy
AU  - Savić, Miroslav
AU  - Mihovilović, Marko D.
AU  - Ernst, Margot
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2875
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression
VL  - 254
UR  - https://hdl.handle.net/21.15107/rcub_farfar_2875
ER  - 

@conference{
author = "Knutson, Daniel and Verma, Ranjit and Stephen, Michael and Kodali, Revathi and Arnold, Leggy and Savić, Miroslav and Mihovilović, Marko D. and Ernst, Margot and Sieghart, Werner and Cook, James M.",
year = "2017",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression",
volume = "254",
url = "https://hdl.handle.net/21.15107/rcub_farfar_2875"
}

Knutson, D., Verma, R., Stephen, M., Kodali, R., Arnold, L., Savić, M., Mihovilović, M. D., Ernst, M., Sieghart, W.,& Cook, J. M.. (2017). Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 254.
https://hdl.handle.net/21.15107/rcub_farfar_2875

Knutson D, Verma R, Stephen M, Kodali R, Arnold L, Savić M, Mihovilović MD, Ernst M, Sieghart W, Cook JM. Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression. in Abstracts of Papers of the American Chemical Society. 2017;254.
https://hdl.handle.net/21.15107/rcub_farfar_2875 .

Knutson, Daniel, Verma, Ranjit, Stephen, Michael, Kodali, Revathi, Arnold, Leggy, Savić, Miroslav, Mihovilović, Marko D., Ernst, Margot, Sieghart, Werner, Cook, James M., "Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression" in Abstracts of Papers of the American Chemical Society, 254 (2017),
https://hdl.handle.net/21.15107/rcub_farfar_2875 .

TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Poe, Michael M.
AU  - Ramerstorfer, Joachim
AU  - Varagić, Zdravko
AU  - Namjoshi, Ojas A.
AU  - Batinić, Bojan
AU  - Radulović, Tamara
AU  - Marković, Bojan
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2200
AB  - Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects
VL  - 1554
SP  - 36
EP  - 48
DO  - 10.1016/j.brainres.2014.01.036
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Poe, Michael M. and Ramerstorfer, Joachim and Varagić, Zdravko and Namjoshi, Ojas A. and Batinić, Bojan and Radulović, Tamara and Marković, Bojan and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2014",
abstract = "Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects",
volume = "1554",
pages = "36-48",
doi = "10.1016/j.brainres.2014.01.036"
}

Obradović, A., Joksimović, S., Poe, M. M., Ramerstorfer, J., Varagić, Z., Namjoshi, O. A., Batinić, B., Radulović, T., Marković, B., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2014). Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research
Elsevier Science BV, Amsterdam., 1554, 36-48.
https://doi.org/10.1016/j.brainres.2014.01.036

Obradović A, Joksimović S, Poe MM, Ramerstorfer J, Varagić Z, Namjoshi OA, Batinić B, Radulović T, Marković B, Roth BL, Sieghart W, Cook JM, Savić M. Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research. 2014;1554:36-48.
doi:10.1016/j.brainres.2014.01.036 .

Obradović, Aleksandar, Joksimović, Srđan, Poe, Michael M., Ramerstorfer, Joachim, Varagić, Zdravko, Namjoshi, Ojas A., Batinić, Bojan, Radulović, Tamara, Marković, Bojan, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects" in Brain Research, 1554 (2014):36-48,
https://doi.org/10.1016/j.brainres.2014.01.036 . .

TY  - CONF
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Poe, Michael M.
AU  - Biawat, Poonam
AU  - Ramerstorfer, Joachim
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1887
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors
VL  - 23
IS  - Supplement 2
SP  - S259
EP  - S260
DO  - 10.1016/S0924-977X(13)70405-X
ER  - 

@conference{
author = "Timić, Tamara and Joksimović, Srđan and Obradović, Aleksandar and Poe, Michael M. and Biawat, Poonam and Ramerstorfer, Joachim and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors",
volume = "23",
number = "Supplement 2",
pages = "S259-S260",
doi = "10.1016/S0924-977X(13)70405-X"
}

Timić, T., Joksimović, S., Obradović, A., Poe, M. M., Biawat, P., Ramerstorfer, J., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S259-S260.
https://doi.org/10.1016/S0924-977X(13)70405-X

Timić T, Joksimović S, Obradović A, Poe MM, Biawat P, Ramerstorfer J, Roth BL, Sieghart W, Cook JM, Savić M. MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology. 2013;23(Supplement 2):S259-S260.
doi:10.1016/S0924-977X(13)70405-X .

Timić, Tamara, Joksimović, Srđan, Obradović, Aleksandar, Poe, Michael M., Biawat, Poonam, Ramerstorfer, Joachim, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S259-S260,
https://doi.org/10.1016/S0924-977X(13)70405-X . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Divljaković, Jovana
AU  - van Linn, Michael
AU  - Varagić, Zdravko
AU  - Brajković, Gordana
AU  - Milinković, Marija M.
AU  - Yin, Wenyuan
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2028
AB  - Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α 1 -subunit affinity-selective antagonist Β-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α 1 -subunit selective ligand-WYS8 (0.2, 1 and 10mg/kg), on its own and in combination with the non-selective agonist DZP (2mg/kg) or Β-CCt (5mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α 1 -subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with Β-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.
T2  - European Neuropsychopharmacology
T1  - Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors
VL  - 23
IS  - 5
SP  - 390
EP  - 399
DO  - 10.1016/j.euroneuro.2012.05.003
ER  - 

@article{
author = "Joksimović, Srđan and Divljaković, Jovana and van Linn, Michael and Varagić, Zdravko and Brajković, Gordana and Milinković, Marija M. and Yin, Wenyuan and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α 1 -subunit affinity-selective antagonist Β-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α 1 -subunit selective ligand-WYS8 (0.2, 1 and 10mg/kg), on its own and in combination with the non-selective agonist DZP (2mg/kg) or Β-CCt (5mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α 1 -subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with Β-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.",
journal = "European Neuropsychopharmacology",
title = "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors",
volume = "23",
number = "5",
pages = "390-399",
doi = "10.1016/j.euroneuro.2012.05.003"
}

Joksimović, S., Divljaković, J., van Linn, M., Varagić, Z., Brajković, G., Milinković, M. M., Yin, W., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology, 23(5), 390-399.
https://doi.org/10.1016/j.euroneuro.2012.05.003

Joksimović S, Divljaković J, van Linn M, Varagić Z, Brajković G, Milinković MM, Yin W, Timić T, Sieghart W, Cook JM, Savić M. Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology. 2013;23(5):390-399.
doi:10.1016/j.euroneuro.2012.05.003 .

Joksimović, Srđan, Divljaković, Jovana, van Linn, Michael, Varagić, Zdravko, Brajković, Gordana, Milinković, Marija M., Yin, Wenyuan, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors" in European Neuropsychopharmacology, 23, no. 5 (2013):390-399,
https://doi.org/10.1016/j.euroneuro.2012.05.003 . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Varagić, Zdravko
AU  - Kovacević, Jovana
AU  - van Linn, Michael
AU  - Milić, Marija
AU  - Rallapalli, Sundari
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1839
AB  - Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.
PB  - Springer, New York
T2  - QSAR & Combinatorial Science
T1  - Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?
VL  - 230
IS  - 1
SP  - 113
EP  - 123
DO  - 10.1007/s00213-013-3143-4
ER  - 

@article{
author = "Joksimović, Srđan and Varagić, Zdravko and Kovacević, Jovana and van Linn, Michael and Milić, Marija and Rallapalli, Sundari and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.",
publisher = "Springer, New York",
journal = "QSAR & Combinatorial Science",
title = "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?",
volume = "230",
number = "1",
pages = "113-123",
doi = "10.1007/s00213-013-3143-4"
}

Joksimović, S., Varagić, Z., Kovacević, J., van Linn, M., Milić, M., Rallapalli, S., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science
Springer, New York., 230(1), 113-123.
https://doi.org/10.1007/s00213-013-3143-4

Joksimović S, Varagić Z, Kovacević J, van Linn M, Milić M, Rallapalli S, Timić T, Sieghart W, Cook JM, Savić M. Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science. 2013;230(1):113-123.
doi:10.1007/s00213-013-3143-4 .

Joksimović, Srđan, Varagić, Zdravko, Kovacević, Jovana, van Linn, Michael, Milić, Marija, Rallapalli, Sundari, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?" in QSAR & Combinatorial Science, 230, no. 1 (2013):113-123,
https://doi.org/10.1007/s00213-013-3143-4 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Huang, Shengming
AU  - Ramerstorfer, Joachim
AU  - Milinković, Marija M.
AU  - Divljaković, Jovana
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Savić, Miroslav
AU  - Cook, James M.
PY  - 2010
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1350
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - SH-I-048A, a novel positive modulator of GABA-A receptor: in vitro and behavioral profile
VL  - 20
IS  - Supplement 3
SP  - S260
EP  - S260
DO  - 10.1016/S0924-977X(10)70331-X
ER  - 

@conference{
author = "Joksimović, Srđan and Huang, Shengming and Ramerstorfer, Joachim and Milinković, Marija M. and Divljaković, Jovana and Roth, Brian L. and Sieghart, Werner and Savić, Miroslav and Cook, James M.",
year = "2010",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "SH-I-048A, a novel positive modulator of GABA-A receptor: in vitro and behavioral profile",
volume = "20",
number = "Supplement 3",
pages = "S260-S260",
doi = "10.1016/S0924-977X(10)70331-X"
}

Joksimović, S., Huang, S., Ramerstorfer, J., Milinković, M. M., Divljaković, J., Roth, B. L., Sieghart, W., Savić, M.,& Cook, J. M.. (2010). SH-I-048A, a novel positive modulator of GABA-A receptor: in vitro and behavioral profile. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 20(Supplement 3), S260-S260.
https://doi.org/10.1016/S0924-977X(10)70331-X

Joksimović S, Huang S, Ramerstorfer J, Milinković MM, Divljaković J, Roth BL, Sieghart W, Savić M, Cook JM. SH-I-048A, a novel positive modulator of GABA-A receptor: in vitro and behavioral profile. in European Neuropsychopharmacology. 2010;20(Supplement 3):S260-S260.
doi:10.1016/S0924-977X(10)70331-X .

Joksimović, Srđan, Huang, Shengming, Ramerstorfer, Joachim, Milinković, Marija M., Divljaković, Jovana, Roth, Brian L., Sieghart, Werner, Savić, Miroslav, Cook, James M., "SH-I-048A, a novel positive modulator of GABA-A receptor: in vitro and behavioral profile" in European Neuropsychopharmacology, 20, no. Supplement 3 (2010):S260-S260,
https://doi.org/10.1016/S0924-977X(10)70331-X . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Majumder, Samarpan
AU  - Huang, Shengming
AU  - Edwankar, Rahul V.
AU  - Furtmueller, Roman
AU  - Joksimović, Srđan
AU  - Clayton, Terry
AU  - Ramerstorfer, Joachim
AU  - Milinković, Marija M.
AU  - Roth, Bryan L.
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2010
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1380
AB  - Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Progress in Nutrition
T1  - Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?
VL  - 34
IS  - 2
SP  - 376
EP  - 386
DO  - 10.1016/j.pnpbp.2010.01.004
ER  - 

@article{
author = "Savić, Miroslav and Majumder, Samarpan and Huang, Shengming and Edwankar, Rahul V. and Furtmueller, Roman and Joksimović, Srđan and Clayton, Terry and Ramerstorfer, Joachim and Milinković, Marija M. and Roth, Bryan L. and Sieghart, Werner and Cook, James M.",
year = "2010",
abstract = "Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Progress in Nutrition",
title = "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?",
volume = "34",
number = "2",
pages = "376-386",
doi = "10.1016/j.pnpbp.2010.01.004"
}

Savić, M., Majumder, S., Huang, S., Edwankar, R. V., Furtmueller, R., Joksimović, S., Clayton, T., Ramerstorfer, J., Milinković, M. M., Roth, B. L., Sieghart, W.,& Cook, J. M.. (2010). Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition
Pergamon-Elsevier Science Ltd, Oxford., 34(2), 376-386.
https://doi.org/10.1016/j.pnpbp.2010.01.004

Savić M, Majumder S, Huang S, Edwankar RV, Furtmueller R, Joksimović S, Clayton T, Ramerstorfer J, Milinković MM, Roth BL, Sieghart W, Cook JM. Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition. 2010;34(2):376-386.
doi:10.1016/j.pnpbp.2010.01.004 .

Savić, Miroslav, Majumder, Samarpan, Huang, Shengming, Edwankar, Rahul V., Furtmueller, Roman, Joksimović, Srđan, Clayton, Terry, Ramerstorfer, Joachim, Milinković, Marija M., Roth, Bryan L., Sieghart, Werner, Cook, James M., "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?" in Progress in Nutrition, 34, no. 2 (2010):376-386,
https://doi.org/10.1016/j.pnpbp.2010.01.004 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Savić, Miroslav
AU  - Milinković, Marija M.
AU  - van Linn, Michael
AU  - Ramerstorfer, Joachim
AU  - Majumder, Samarpan
AU  - Yin, Wenyuan
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2009
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1172
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - WYS-8, a novel ligand at GABAA receptors: a step forward to linking in vitro with in vivo selectivity?
VL  - 19
IS  - Supplement 3
SP  - S297
EP  - S297
DO  - 10.1016/S0924-977X(09)70440-7
ER  - 

@conference{
author = "Joksimović, Srđan and Savić, Miroslav and Milinković, Marija M. and van Linn, Michael and Ramerstorfer, Joachim and Majumder, Samarpan and Yin, Wenyuan and Roth, Brian L. and Sieghart, Werner and Cook, James M.",
year = "2009",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "WYS-8, a novel ligand at GABAA receptors: a step forward to linking in vitro with in vivo selectivity?",
volume = "19",
number = "Supplement 3",
pages = "S297-S297",
doi = "10.1016/S0924-977X(09)70440-7"
}

Joksimović, S., Savić, M., Milinković, M. M., van Linn, M., Ramerstorfer, J., Majumder, S., Yin, W., Roth, B. L., Sieghart, W.,& Cook, J. M.. (2009). WYS-8, a novel ligand at GABAA receptors: a step forward to linking in vitro with in vivo selectivity?. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 19(Supplement 3), S297-S297.
https://doi.org/10.1016/S0924-977X(09)70440-7

Joksimović S, Savić M, Milinković MM, van Linn M, Ramerstorfer J, Majumder S, Yin W, Roth BL, Sieghart W, Cook JM. WYS-8, a novel ligand at GABAA receptors: a step forward to linking in vitro with in vivo selectivity?. in European Neuropsychopharmacology. 2009;19(Supplement 3):S297-S297.
doi:10.1016/S0924-977X(09)70440-7 .

Joksimović, Srđan, Savić, Miroslav, Milinković, Marija M., van Linn, Michael, Ramerstorfer, Joachim, Majumder, Samarpan, Yin, Wenyuan, Roth, Brian L., Sieghart, Werner, Cook, James M., "WYS-8, a novel ligand at GABAA receptors: a step forward to linking in vitro with in vivo selectivity?" in European Neuropsychopharmacology, 19, no. Supplement 3 (2009):S297-S297,
https://doi.org/10.1016/S0924-977X(09)70440-7 . .

TY  - CONF
AU  - Milinković, Marija M.
AU  - Savić, Miroslav
AU  - Huang, Shengming
AU  - Furtmueller, Roman
AU  - Majumder, Samarpan
AU  - Samardžić, Janko
AU  - Divljaković, Jovana
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2009
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1173
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Jy-xhe-053, a benzodiazepine ligand less efficacious at GABAA receptors containing alpha1 and alpha5 than alpha2 and alpha3 subunits
VL  - 19
IS  - Supplement 3
SP  - S296
EP  - S296
DO  - 10.1016/S0924-977X(09)70438-9
ER  - 

@conference{
author = "Milinković, Marija M. and Savić, Miroslav and Huang, Shengming and Furtmueller, Roman and Majumder, Samarpan and Samardžić, Janko and Divljaković, Jovana and Roth, Brian L. and Sieghart, Werner and Cook, James M.",
year = "2009",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Jy-xhe-053, a benzodiazepine ligand less efficacious at GABAA receptors containing alpha1 and alpha5 than alpha2 and alpha3 subunits",
volume = "19",
number = "Supplement 3",
pages = "S296-S296",
doi = "10.1016/S0924-977X(09)70438-9"
}

Milinković, M. M., Savić, M., Huang, S., Furtmueller, R., Majumder, S., Samardžić, J., Divljaković, J., Roth, B. L., Sieghart, W.,& Cook, J. M.. (2009). Jy-xhe-053, a benzodiazepine ligand less efficacious at GABAA receptors containing alpha1 and alpha5 than alpha2 and alpha3 subunits. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 19(Supplement 3), S296-S296.
https://doi.org/10.1016/S0924-977X(09)70438-9

Milinković MM, Savić M, Huang S, Furtmueller R, Majumder S, Samardžić J, Divljaković J, Roth BL, Sieghart W, Cook JM. Jy-xhe-053, a benzodiazepine ligand less efficacious at GABAA receptors containing alpha1 and alpha5 than alpha2 and alpha3 subunits. in European Neuropsychopharmacology. 2009;19(Supplement 3):S296-S296.
doi:10.1016/S0924-977X(09)70438-9 .

Milinković, Marija M., Savić, Miroslav, Huang, Shengming, Furtmueller, Roman, Majumder, Samarpan, Samardžić, Janko, Divljaković, Jovana, Roth, Brian L., Sieghart, Werner, Cook, James M., "Jy-xhe-053, a benzodiazepine ligand less efficacious at GABAA receptors containing alpha1 and alpha5 than alpha2 and alpha3 subunits" in European Neuropsychopharmacology, 19, no. Supplement 3 (2009):S296-S296,
https://doi.org/10.1016/S0924-977X(09)70438-9 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Huang, Shengming
AU  - Ara, S.
AU  - van Linn, Michael
AU  - Milinković, Marija M.
AU  - Bokonjić, Dubravko
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1079
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Relative contribution of the alpha2-, 3-and 5-containing GABAA receptors to benzodiazepine effects in the water maze
VL  - 18
IS  - Supplement 4
SP  - S282
EP  - S282
DO  - 10.1016/S0924-977X(08)70372-9
ER  - 

@conference{
author = "Joksimović, Srđan and Savić, Miroslav and Clayton, Terry and Huang, Shengming and Ara, S. and van Linn, Michael and Milinković, Marija M. and Bokonjić, Dubravko and Sieghart, Werner and Cook, James M.",
year = "2008",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Relative contribution of the alpha2-, 3-and 5-containing GABAA receptors to benzodiazepine effects in the water maze",
volume = "18",
number = "Supplement 4",
pages = "S282-S282",
doi = "10.1016/S0924-977X(08)70372-9"
}

Joksimović, S., Savić, M., Clayton, T., Huang, S., Ara, S., van Linn, M., Milinković, M. M., Bokonjić, D., Sieghart, W.,& Cook, J. M.. (2008). Relative contribution of the alpha2-, 3-and 5-containing GABAA receptors to benzodiazepine effects in the water maze. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 18(Supplement 4), S282-S282.
https://doi.org/10.1016/S0924-977X(08)70372-9

Joksimović S, Savić M, Clayton T, Huang S, Ara S, van Linn M, Milinković MM, Bokonjić D, Sieghart W, Cook JM. Relative contribution of the alpha2-, 3-and 5-containing GABAA receptors to benzodiazepine effects in the water maze. in European Neuropsychopharmacology. 2008;18(Supplement 4):S282-S282.
doi:10.1016/S0924-977X(08)70372-9 .

Joksimović, Srđan, Savić, Miroslav, Clayton, Terry, Huang, Shengming, Ara, S., van Linn, Michael, Milinković, Marija M., Bokonjić, Dubravko, Sieghart, Werner, Cook, James M., "Relative contribution of the alpha2-, 3-and 5-containing GABAA receptors to benzodiazepine effects in the water maze" in European Neuropsychopharmacology, 18, no. Supplement 4 (2008):S282-S282,
https://doi.org/10.1016/S0924-977X(08)70372-9 . .

TY  - CONF
AU  - Samardžić, Janko
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Rallapalli, Sundari
AU  - Obradović, Dragan I.
AU  - Joksimović, Srđan
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1025
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of a novel inverse agonist selective for alpha5 GABAA receptors on spatial memory: comparison with the standard non-selective inverse agonist DMCM
VL  - 18
IS  - Supplement 4
SP  - S285
EP  - S285
DO  - 10.1016/S0924-977X(08)70377-8
ER  - 

@conference{
author = "Samardžić, Janko and Savić, Miroslav and Clayton, Terry and Rallapalli, Sundari and Obradović, Dragan I. and Joksimović, Srđan and Sieghart, Werner and Cook, James M.",
year = "2008",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of a novel inverse agonist selective for alpha5 GABAA receptors on spatial memory: comparison with the standard non-selective inverse agonist DMCM",
volume = "18",
number = "Supplement 4",
pages = "S285-S285",
doi = "10.1016/S0924-977X(08)70377-8"
}

Samardžić, J., Savić, M., Clayton, T., Rallapalli, S., Obradović, D. I., Joksimović, S., Sieghart, W.,& Cook, J. M.. (2008). Effects of a novel inverse agonist selective for alpha5 GABAA receptors on spatial memory: comparison with the standard non-selective inverse agonist DMCM. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 18(Supplement 4), S285-S285.
https://doi.org/10.1016/S0924-977X(08)70377-8

Samardžić J, Savić M, Clayton T, Rallapalli S, Obradović DI, Joksimović S, Sieghart W, Cook JM. Effects of a novel inverse agonist selective for alpha5 GABAA receptors on spatial memory: comparison with the standard non-selective inverse agonist DMCM. in European Neuropsychopharmacology. 2008;18(Supplement 4):S285-S285.
doi:10.1016/S0924-977X(08)70377-8 .

Samardžić, Janko, Savić, Miroslav, Clayton, Terry, Rallapalli, Sundari, Obradović, Dragan I., Joksimović, Srđan, Sieghart, Werner, Cook, James M., "Effects of a novel inverse agonist selective for alpha5 GABAA receptors on spatial memory: comparison with the standard non-selective inverse agonist DMCM" in European Neuropsychopharmacology, 18, no. Supplement 4 (2008):S285-S285,
https://doi.org/10.1016/S0924-977X(08)70377-8 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Furtmueller, Roman
AU  - Gaurilović, Ivana
AU  - Samardžić, Janko
AU  - Savić, Snežana
AU  - Huck, Sigismund
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1081
AB  - Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats
VL  - 1208
SP  - 150
EP  - 159
DO  - 10.1016/j.brainres.2008.02.020
ER  - 

@article{
author = "Savić, Miroslav and Clayton, Terry and Furtmueller, Roman and Gaurilović, Ivana and Samardžić, Janko and Savić, Snežana and Huck, Sigismund and Sieghart, Werner and Cook, James M.",
year = "2008",
abstract = "Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats",
volume = "1208",
pages = "150-159",
doi = "10.1016/j.brainres.2008.02.020"
}

Savić, M., Clayton, T., Furtmueller, R., Gaurilović, I., Samardžić, J., Savić, S., Huck, S., Sieghart, W.,& Cook, J. M.. (2008). PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research
Elsevier Science BV, Amsterdam., 1208, 150-159.
https://doi.org/10.1016/j.brainres.2008.02.020

Savić M, Clayton T, Furtmueller R, Gaurilović I, Samardžić J, Savić S, Huck S, Sieghart W, Cook JM. PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research. 2008;1208:150-159.
doi:10.1016/j.brainres.2008.02.020 .

Savić, Miroslav, Clayton, Terry, Furtmueller, Roman, Gaurilović, Ivana, Samardžić, Janko, Savić, Snežana, Huck, Sigismund, Sieghart, Werner, Cook, James M., "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats" in Brain Research, 1208 (2008):150-159,
https://doi.org/10.1016/j.brainres.2008.02.020 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Huang, Shengming
AU  - Furtmueller, Roman
AU  - Clayton, Terry
AU  - Huck, Sigismund
AU  - Obradović, Dragan I.
AU  - Ugrešić, Nenad
AU  - Sieghart, Werner
AU  - Bokonjić, Dubravko
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1048
AB  - Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.
PB  - Nature Publishing Group, London
T2  - Neuropsychopharmacology
T1  - Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?
VL  - 33
IS  - 2
SP  - 332
EP  - 339
DO  - 10.1038/sj.npp.1301403
ER  - 

@article{
author = "Savić, Miroslav and Huang, Shengming and Furtmueller, Roman and Clayton, Terry and Huck, Sigismund and Obradović, Dragan I. and Ugrešić, Nenad and Sieghart, Werner and Bokonjić, Dubravko and Cook, James M.",
year = "2008",
abstract = "Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.",
publisher = "Nature Publishing Group, London",
journal = "Neuropsychopharmacology",
title = "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?",
volume = "33",
number = "2",
pages = "332-339",
doi = "10.1038/sj.npp.1301403"
}

Savić, M., Huang, S., Furtmueller, R., Clayton, T., Huck, S., Obradović, D. I., Ugrešić, N., Sieghart, W., Bokonjić, D.,& Cook, J. M.. (2008). Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology
Nature Publishing Group, London., 33(2), 332-339.
https://doi.org/10.1038/sj.npp.1301403

Savić M, Huang S, Furtmueller R, Clayton T, Huck S, Obradović DI, Ugrešić N, Sieghart W, Bokonjić D, Cook JM. Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology. 2008;33(2):332-339.
doi:10.1038/sj.npp.1301403 .

Savić, Miroslav, Huang, Shengming, Furtmueller, Roman, Clayton, Terry, Huck, Sigismund, Obradović, Dragan I., Ugrešić, Nenad, Sieghart, Werner, Bokonjić, Dubravko, Cook, James M., "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?" in Neuropsychopharmacology, 33, no. 2 (2008):332-339,
https://doi.org/10.1038/sj.npp.1301403 . .

TY  - CONF
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Furtmueller, Roman
AU  - Gavrilović, I.
AU  - Savić, Snežana
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2007
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/897
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Electrophysiological and behavioral profile of a GABAA alpha5 subtype-functionally selective negative modulator
VL  - 17
IS  - Supplement 4
SP  - S265
EP  - S265
DO  - 10.1016/S0924-977X(07)70364-4
ER  - 

@conference{
author = "Savić, Miroslav and Clayton, Terry and Furtmueller, Roman and Gavrilović, I. and Savić, Snežana and Sieghart, Werner and Cook, James M.",
year = "2007",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Electrophysiological and behavioral profile of a GABAA alpha5 subtype-functionally selective negative modulator",
volume = "17",
number = "Supplement 4",
pages = "S265-S265",
doi = "10.1016/S0924-977X(07)70364-4"
}

Savić, M., Clayton, T., Furtmueller, R., Gavrilović, I., Savić, S., Sieghart, W.,& Cook, J. M.. (2007). Electrophysiological and behavioral profile of a GABAA alpha5 subtype-functionally selective negative modulator. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 17(Supplement 4), S265-S265.
https://doi.org/10.1016/S0924-977X(07)70364-4

Savić M, Clayton T, Furtmueller R, Gavrilović I, Savić S, Sieghart W, Cook JM. Electrophysiological and behavioral profile of a GABAA alpha5 subtype-functionally selective negative modulator. in European Neuropsychopharmacology. 2007;17(Supplement 4):S265-S265.
doi:10.1016/S0924-977X(07)70364-4 .

Savić, Miroslav, Clayton, Terry, Furtmueller, Roman, Gavrilović, I., Savić, Snežana, Sieghart, Werner, Cook, James M., "Electrophysiological and behavioral profile of a GABAA alpha5 subtype-functionally selective negative modulator" in European Neuropsychopharmacology, 17, no. Supplement 4 (2007):S265-S265,
https://doi.org/10.1016/S0924-977X(07)70364-4 . .

TY  - CONF
AU  - Huang, Shengming
AU  - Savić, Miroslav
AU  - Furtmueller, Roman
AU  - Duke, Angela
AU  - Clayton, Terry
AU  - Sieghart, Werner
AU  - Rowlett, James K.
AU  - Cook, James M.
PY  - 2007
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/940
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands
VL  - 233
SP  - 728
EP  - 728
UR  - https://hdl.handle.net/21.15107/rcub_farfar_940
ER  - 

@conference{
author = "Huang, Shengming and Savić, Miroslav and Furtmueller, Roman and Duke, Angela and Clayton, Terry and Sieghart, Werner and Rowlett, James K. and Cook, James M.",
year = "2007",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands",
volume = "233",
pages = "728-728",
url = "https://hdl.handle.net/21.15107/rcub_farfar_940"
}

Huang, S., Savić, M., Furtmueller, R., Duke, A., Clayton, T., Sieghart, W., Rowlett, J. K.,& Cook, J. M.. (2007). Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 233, 728-728.
https://hdl.handle.net/21.15107/rcub_farfar_940

Huang S, Savić M, Furtmueller R, Duke A, Clayton T, Sieghart W, Rowlett JK, Cook JM. Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands. in Abstracts of Papers of the American Chemical Society. 2007;233:728-728.
https://hdl.handle.net/21.15107/rcub_farfar_940 .

Huang, Shengming, Savić, Miroslav, Furtmueller, Roman, Duke, Angela, Clayton, Terry, Sieghart, Werner, Rowlett, James K., Cook, James M., "Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands" in Abstracts of Papers of the American Chemical Society, 233 (2007):728-728,
https://hdl.handle.net/21.15107/rcub_farfar_940 .