Allopregnanolone , a neurosteroid derived endogeneously in the brain from pregnenolone was discovered to be a potent anesthetic in the early 1940s. Using experimental animals to develop structure-activity relationships, the clinically used steroid anesthetic alphaxalone was subsequently developed in the pharmaceutical industry. However, it was not until the mid-1980s that GABA-A receptors were identified as the molecular targets of these anesthetic steroids. The binding of allopregnanolone and alfaxalone to GABA-A receptors is enantioselective with their mirror images (ent-neurosteroids) having little activity. Further studies of the molecular basis for neurosteroid enantioselectivity at GABA-A receptors has identified which structural features of these two ent-neurosteroids are responsible for their poor binding and anesthetic activity. Using this information, it has been possible to design ent-neurosteriods that have high activity as anesthetics and allosteric modulators of GABA-A receptors. The studies that led to the discovery of these highly potent ent-neurosteroids and the potential advantages that they ,and ent-steroids in general, might have as potential new drugs will be presented. This work was supported in the past by NIH grant P01 GM 47969 and is currently supported by The Taylor Family Institute for Innovative Psychiatric Research.

ent-Neurosteroids: Their use as experimental tools and potential as drugs

251st National Meeting (2016)

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