Pavel Y Savechenkov, David C Chiara, Rooma Desai, Alexander T Stern, Xiaojuan Zhou, Alexis M Ziemba, Andrea L Szabo, Yinghui Zhang, Jonathan B Cohen, Stuart A Forman, Keith W Miller, Karol S Bruzik
Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAA R), but the locations of their GABAA R binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAA R, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAA R responses, left-shifting the GABA concentration - response curve for human α1β3γ2 GABAA Rs expressed in Xenopus oocytes, and enhancing [3 H]muscimol binding to α1β3γ2 GABAA Rs expressed in HEK293 cells...
August 18, 2017: European Journal of Medicinal Chemistry