Development of novel neuroactive steroids for the potential treatment of Neurological Disorders
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 extrasynaptic GABAA receptors. The most potent endogenous NS's at GABAAR's are allopregnanolone (AP) and 5?-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 subtype selective and 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 3?-methyl group and a alternate substitutions at the 11?-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.