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  - 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  - 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 .