SYNTHESIS AND IN-VITRO ACTIVITY OF 3-BETA-SUBSTITUTED-3-ALPHA-HYDROXYPREGNAN-20-ONES - ALLOSTERIC MODULATORS OF THE GABA(A) RECEPTOR

Two naturally occurring metabolites of progesterone, 3 alpha-hydroxy-5 alpha- and 5 beta-pregnan-20-one (1 and 2), are potent allosteric mod ulators of the GABA(A) receptor. Their therapeutic potential as anxiol ytics, anticonvulsants, and sedative/hypnotics is limited by rapid met abolism. To avoid these shortcomings, a series of 3 beta-substituted d erivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5 alpha- and 5 beta-series as determined by inhibition of [S-35]TBPS binding. In the 5 alpha-series, 3 beta-eth yl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as subst ituents of the form 3 beta-XCH(2), where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [S-35]TBPS binding. In the 5 beta-series, the unsubstituted parent 2 is a two-component i nhibitor, whereas all of the 3 beta-substituted derivatives of 2 inhib it TBPS via a single class of binding sites. In addition, all of the 3 -substituted 5 beta-sterols tested are full inhibitors of [S-35]TBPS b inding. Electrophysiological measurements using alpha 1 beta 2 gamma 2 L receptors expressed in oocytes show that 3 beta-methyl- and 3 beta-( azidomethyl)-3 alpha-hydroxy-5 alpha-pregnan-20-one (6 and 22, respect ively) are potent full efficacy modulators and that 3 alpha-hydroxy-3 beta-(trifluoromethyl)-5 alpha-pregnan-20-one (24) is a low-efficacy m odulator, confirming the results obtained from [S-35]TBPS binding. The se results indicate that modification of the 3 beta-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABA(A) re ceptor. In animal studies, compound 6 (CCD 1042) is an orally active a nticonvulsant, while the naturally occurring progesterone metabolites I and 2 are inactive when administered orally, suggesting that 3 beta- substitution slows metabolism of the S-hydroxyl, resulting in orally b ioavailable steroid modulators of the GABA(A) receptor.