Development and SAR of functionally selective allosteric modulators of GABAA receptors
2011
Alhambra, Cristobal | Becker, Chris | Blake, Timothy | Chang, Amy (Hui-Fang) | Damewood, James R., Jr | Daniels, Thalia | Dembofsky, Bruce T. | Gurley, David A. | Hall, James E. | Herzog, Keith J. | Horchler, Carey L. | Ohnmacht, Cyrus J. | Schmiesing, Richard Jon | Dudley, Adam | Ribadeneira, Maria D. | Knappenberger, Katherine S. | Maciag, Carla | Stein, Mark M. | Chopra, Maninder | Liu, Xiaodong F. | Christian, Edward P. | Arriza, Jeffrey L. | Chapdelaine, Marc J.
Positive modulators at the benzodiazepine site of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABAA receptors and that show no functional activity at α1-containing GABAA receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABAA receptors, while simultaneously neutral antagonists at α1-containing GABAA receptors, is described. Such functionally selective modulators of GABAA receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
اظهر المزيد [+] اقل [-]الكلمات المفتاحية الخاصة بالمكنز الزراعي (أجروفوك)
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