Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands

European Journal of Medicinal Chemistry
Pavel Y SavechenkovKarol S Bruzik

Abstract

Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 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 GABAAR responses, left-shifting the GABA concentration - response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [3H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells. With EC50 of 110 nM, 11-AziAP is one the most potent general anesthetics reported. [3H]F4N3Bzoxy-AP and [3H]11-AziAP, at anesthetic concentrations, photoincorporated into α- and β-subunits of purified α1β3γ2 GABAARs, but labeling at the subunit level was not inhibited by alphaxalone (30 μM). The enhancement of photolabeling by 3H-azietomidate and 3H-mTFD-MPAB in the presence of either of the two steroid photoprobes indicates the neurosteroid binding site is different from, but allosterically related to, the etomidate ...Continue Reading

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Citations

Jan 6, 2018·The Journal of Biological Chemistry·Wayland W L ChengAlex S Evers
Jun 17, 2020·The Journal of Biological Chemistry·Selwyn S JayakarJonathan B Cohen
Jan 3, 2018·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Hua-Jun Feng, Stuart A Forman
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zetryana Puteri TachrimMakoto Hashimoto

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