Neuroactive steroids (NS) are defined as steroids active in the central nervous system (CNS). NS were initially identified as metabolites of the hormone progesterone (P) and have been subsequently shown to be potent positive allosteric modulators (PAMS) of synaptic and extrasynaptic GABAA receptors. Some of the most potent endogenous NS’s at GABAAR’s are allopregnanolone (AP) and 5a-THDOC; the principal metabolites of the hormones progesterone and deoxycorticosterone respectively. Considering the physiological importance of AP and THDOC, our laboratory has begun to develop more drug-like analogs of endogenous steroids that have improved potency and reduced hormonal metabolism. Our studies have led to the development of a series of androstane analogs that possess a nitro in the 17-position combined with a 3b-methyl group and alternate substitutions at the 11b-position. The synthesis of these analogs and potency at select GABAA subtypes along with the resulting pharmacokinetic properties will be discussed in addition to the in vivo data from anticonvulsant and substance abuse studies.

Novel 17-substituted neuroactive steroids for the potential treatment of neurological disorders

251st National Meeting (2016)

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