TY  - JOUR
AU  - Gajić Bojić, Milica
AU  - Treven, Marco
AU  - Pandey, Kamal P
AU  - Tiruveedhula, Phani Babu V V N
AU  - Santrač, Anja
AU  - Đukanović, Đorđe
AU  - Vojinović, Nataša
AU  - Amidžić, Ljiljana
AU  - Škrbić, Ranko
AU  - Scholze, Petra
AU  - Ernst, Margot
AU  - Cook, James M
AU  - Savić, Miroslav
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5619
AB  - Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.
PB  - Canadian Science Publishing
T2  - Canadian  Journal of Physiology and  Pharmacology
T1  - Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta
VL  - 102
IS  - 3
SP  - 206
EP  - 217
DO  - 10.1139/cjpp-2023-0285
ER  - 

@article{
author = "Gajić Bojić, Milica and Treven, Marco and Pandey, Kamal P and Tiruveedhula, Phani Babu V V N and Santrač, Anja and Đukanović, Đorđe and Vojinović, Nataša and Amidžić, Ljiljana and Škrbić, Ranko and Scholze, Petra and Ernst, Margot and Cook, James M and Savić, Miroslav",
year = "2024",
abstract = "Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.",
publisher = "Canadian Science Publishing",
journal = "Canadian  Journal of Physiology and  Pharmacology",
title = "Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta",
volume = "102",
number = "3",
pages = "206-217",
doi = "10.1139/cjpp-2023-0285"
}

Gajić Bojić, M., Treven, M., Pandey, K. P., Tiruveedhula, P. B. V. V. N., Santrač, A., Đukanović, Đ., Vojinović, N., Amidžić, L., Škrbić, R., Scholze, P., Ernst, M., Cook, J. M.,& Savić, M.. (2024). Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta. in Canadian  Journal of Physiology and  Pharmacology
Canadian Science Publishing., 102(3), 206-217.
https://doi.org/10.1139/cjpp-2023-0285

Gajić Bojić M, Treven M, Pandey KP, Tiruveedhula PBVVN, Santrač A, Đukanović Đ, Vojinović N, Amidžić L, Škrbić R, Scholze P, Ernst M, Cook JM, Savić M. Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta. in Canadian  Journal of Physiology and  Pharmacology. 2024;102(3):206-217.
doi:10.1139/cjpp-2023-0285 .

Gajić Bojić, Milica, Treven, Marco, Pandey, Kamal P, Tiruveedhula, Phani Babu V V N, Santrač, Anja, Đukanović, Đorđe, Vojinović, Nataša, Amidžić, Ljiljana, Škrbić, Ranko, Scholze, Petra, Ernst, Margot, Cook, James M, Savić, Miroslav, "Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta" in Canadian  Journal of Physiology and  Pharmacology, 102, no. 3 (2024):206-217,
https://doi.org/10.1139/cjpp-2023-0285 . .

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  - Andronis, Christos
AU  - Silva, João
AU  - Lekka, Eftychia
AU  - Virvilis, Vassilis
AU  - Carmo, Helena
AU  - Bampali, Konstantina
AU  - Ernst, Margot
AU  - Hu, Yang
AU  - Loryan, Irena
AU  - Richard, Jacques
AU  - Carvalho, Félix
AU  - Savić, Miroslav
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3613
AB  - Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.
PB  - Springer Nature Switzerland
T2  - Archives of Toxicology
T1  - Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis
VL  - 94
IS  - 8
SP  - 2829
EP  - 2845
DO  - 10.1007/s00204-020-02788-1
ER  - 

@article{
author = "Andronis, Christos and Silva, João and Lekka, Eftychia and Virvilis, Vassilis and Carmo, Helena and Bampali, Konstantina and Ernst, Margot and Hu, Yang and Loryan, Irena and Richard, Jacques and Carvalho, Félix and Savić, Miroslav",
year = "2020",
abstract = "Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.",
publisher = "Springer Nature Switzerland",
journal = "Archives of Toxicology",
title = "Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis",
volume = "94",
number = "8",
pages = "2829-2845",
doi = "10.1007/s00204-020-02788-1"
}

Andronis, C., Silva, J., Lekka, E., Virvilis, V., Carmo, H., Bampali, K., Ernst, M., Hu, Y., Loryan, I., Richard, J., Carvalho, F.,& Savić, M.. (2020). Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis. in Archives of Toxicology
Springer Nature Switzerland., 94(8), 2829-2845.
https://doi.org/10.1007/s00204-020-02788-1

Andronis C, Silva J, Lekka E, Virvilis V, Carmo H, Bampali K, Ernst M, Hu Y, Loryan I, Richard J, Carvalho F, Savić M. Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis. in Archives of Toxicology. 2020;94(8):2829-2845.
doi:10.1007/s00204-020-02788-1 .

Andronis, Christos, Silva, João, Lekka, Eftychia, Virvilis, Vassilis, Carmo, Helena, Bampali, Konstantina, Ernst, Margot, Hu, Yang, Loryan, Irena, Richard, Jacques, Carvalho, Félix, Savić, Miroslav, "Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis" in Archives of Toxicology, 94, no. 8 (2020):2829-2845,
https://doi.org/10.1007/s00204-020-02788-1 . .

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  - JOUR
AU  - Batinić, Bojan
AU  - Stanković, Tamara
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Tiruveedhula, Veera V.
AU  - Li, Guanguan
AU  - Scholze, Petra
AU  - Marković, Bojan
AU  - Obradović, Aleksandar
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3070
AB  - It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.
PB  - Elsevier Science BV, Amsterdam
T2  - European Neuropsychopharmacology
T1  - Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!
VL  - 28
IS  - 8
SP  - 903
EP  - 914
DO  - 10.1016/j.euroneuro.2018.05.014
ER  - 

@article{
author = "Batinić, Bojan and Stanković, Tamara and Stephen, Michael and Kodali, Revathi and Tiruveedhula, Veera V. and Li, Guanguan and Scholze, Petra and Marković, Bojan and Obradović, Aleksandar and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
abstract = "It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!",
volume = "28",
number = "8",
pages = "903-914",
doi = "10.1016/j.euroneuro.2018.05.014"
}

Batinić, B., Stanković, T., Stephen, M., Kodali, R., Tiruveedhula, V. V., Li, G., Scholze, P., Marković, B., Obradović, A., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 28(8), 903-914.
https://doi.org/10.1016/j.euroneuro.2018.05.014

Batinić B, Stanković T, Stephen M, Kodali R, Tiruveedhula VV, Li G, Scholze P, Marković B, Obradović A, Ernst M, Cook JM, Savić M. Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology. 2018;28(8):903-914.
doi:10.1016/j.euroneuro.2018.05.014 .

Batinić, Bojan, Stanković, Tamara, Stephen, Michael, Kodali, Revathi, Tiruveedhula, Veera V., Li, Guanguan, Scholze, Petra, Marković, Bojan, Obradović, Aleksandar, Ernst, Margot, Cook, James M., Savić, Miroslav, "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!" in European Neuropsychopharmacology, 28, no. 8 (2018):903-914,
https://doi.org/10.1016/j.euroneuro.2018.05.014 . .

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  - 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  - Timić-Stamenić, Tamara
AU  - Poe, Michael M.
AU  - Rehman, Sabah
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Scholze, Petra
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2631
AB  - We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.
PB  - Elsevier Science BV, Amsterdam
T2  - European Journal of Pharmacology
T1  - Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit
VL  - 791
SP  - 433
EP  - 443
DO  - 10.1016/j.ejphar.2016.09.016
ER  - 

@article{
author = "Timić-Stamenić, Tamara and Poe, Michael M. and Rehman, Sabah and Santrač, Anja and Divović, Branka and Scholze, Petra and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2016",
abstract = "We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Journal of Pharmacology",
title = "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit",
volume = "791",
pages = "433-443",
doi = "10.1016/j.ejphar.2016.09.016"
}

Timić-Stamenić, T., Poe, M. M., Rehman, S., Santrač, A., Divović, B., Scholze, P., Ernst, M., Cook, J. M.,& Savić, M.. (2016). Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology
Elsevier Science BV, Amsterdam., 791, 433-443.
https://doi.org/10.1016/j.ejphar.2016.09.016

Timić-Stamenić T, Poe MM, Rehman S, Santrač A, Divović B, Scholze P, Ernst M, Cook JM, Savić M. Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology. 2016;791:433-443.
doi:10.1016/j.ejphar.2016.09.016 .

Timić-Stamenić, Tamara, Poe, Michael M., Rehman, Sabah, Santrač, Anja, Divović, Branka, Scholze, Petra, Ernst, Margot, Cook, James M., Savić, Miroslav, "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit" in European Journal of Pharmacology, 791 (2016):433-443,
https://doi.org/10.1016/j.ejphar.2016.09.016 . .

TY  - CONF
AU  - Poe, Michael M.
AU  - Gallos, George
AU  - Puthenkalam, Roshan
AU  - Savić, Miroslav
AU  - Emala, Charles
AU  - Ernst, Margot
AU  - Cook, James M.
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2510
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Imidazobenzodiazepines for improving alpha 5-GABAAR subtype selectivity and their pharmacological relevance
VL  - 250
UR  - https://hdl.handle.net/21.15107/rcub_farfar_2510
ER  - 

@conference{
author = "Poe, Michael M. and Gallos, George and Puthenkalam, Roshan and Savić, Miroslav and Emala, Charles and Ernst, Margot and Cook, James M.",
year = "2015",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Imidazobenzodiazepines for improving alpha 5-GABAAR subtype selectivity and their pharmacological relevance",
volume = "250",
url = "https://hdl.handle.net/21.15107/rcub_farfar_2510"
}

Poe, M. M., Gallos, G., Puthenkalam, R., Savić, M., Emala, C., Ernst, M.,& Cook, J. M.. (2015). Imidazobenzodiazepines for improving alpha 5-GABAAR subtype selectivity and their pharmacological relevance. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 250.
https://hdl.handle.net/21.15107/rcub_farfar_2510

Poe MM, Gallos G, Puthenkalam R, Savić M, Emala C, Ernst M, Cook JM. Imidazobenzodiazepines for improving alpha 5-GABAAR subtype selectivity and their pharmacological relevance. in Abstracts of Papers of the American Chemical Society. 2015;250.
https://hdl.handle.net/21.15107/rcub_farfar_2510 .

Poe, Michael M., Gallos, George, Puthenkalam, Roshan, Savić, Miroslav, Emala, Charles, Ernst, Margot, Cook, James M., "Imidazobenzodiazepines for improving alpha 5-GABAAR subtype selectivity and their pharmacological relevance" in Abstracts of Papers of the American Chemical Society, 250 (2015),
https://hdl.handle.net/21.15107/rcub_farfar_2510 .