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  - 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 .