ROXY-3-BETA-(PHENYLETHYNYL)-5-BETA-PREGNAN-20-ONES - SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF NEUROACTIVE STEROIDS WITH HIGH-AFFINITY FOR GABA(A) RECEPTORS

Neuroactive steroids that allosterically modulate GABA(A) receptors ha ve potential uses as anticonvulsants, anxiolytics, and sedative-hypnot ic agents. Recently, a series of pregnanes substituted with simple alk yl groups at the 3 beta-position were synthesized and found to be acti ve in vitro. The present report describes the synthesis of a series of substituted 3 alpha-hydroxy-3 beta-(phenylethynyl)pregnan-20-ones and their in vitro structure-activity relationship determined by their po tency for inhibition of [S-35]TBPS binding in rat brain membranes. App ropriate substitution of the phenyl group results in ligands with part icularly high affinity for the neuroactive steroid site on GABA(A) rec eptors (e.g., 4-acetyl 28, IC50 10 nM). The potency of selected steroi ds was confirmed electrophysiologically in oocytes expressing cloned h uman GABA(A) alpha 1 beta 2 gamma 2L receptors (e.g., compound 28, EC( 50) 6.6 nM). Consistent with their in vitro activity, some of the 3 be ta-(phenylethynyl)-substituted steroids displayed anticonvulsant activ ity in the pentylenetetrazol (PTZ) and maximal electroshock (MES) test s following ip administration in mice. Notably, the 3 beta-[(4-acetylp henyl)ethynyl]-19-nor derivative 36 demonstrated an attractive anticon vulsant profile (PTZ and MES ED(50) values of 2.8 and 9.2 mg/kg, respe ctively). A new pharmacophore for the neuroactive steroid site of GABA (A) receptors is proposed based upon the high affinity of certain subs tituted 3 beta-(phenylethynyl) steroids.