ENANTIOSELECTIVE BLOCKADE OF T-TYPE CA2-RAT SENSORY NEURONS BY A STEROID THAT LACKS GAMMA-AMINOBUTYRIC ACID-MODULATORY ACTIVITY( CURRENT INADULT)

A number of steroids seem to have anesthetic effects resulting primari ly from their ability to potentiate currents gated by gamma-aminobutyr ic acid, (GABA(A)) receptor activation. One such compound is (3 alpha, 5 alpha,17 beta)-3-hydroxyandrostane-17-carbonitrile [(+)-ACN]. We wer e interested in whether carbonitrile substitution at other ring positi ons might result in other pharmacological consequences. Here we examin e effects of (3 beta,5 alpha,17 beta)-17-hydroxyestrane-3-carbonitrile [(+)-ECN] on GABA(A) receptors and Ca2+ channels. In contrast to (+)- ACN, (+)-ECN does not potentiate GABA(A)-receptor activated currents, nor does it directly gate GABA(A)-receptor mediated currents. However, both steroids produce an enantioselective reduction of T-type current . (+)-ECN blocked T current with an lc,, value of 0.3 mu M with a maxi mal block of 41 %. (+)-ACN produced a partial block of T current (44% maximal block) with an IC50 value of 0.4 mu M. Block of T current show ed mild use- and voltage-dependence. The (-)-ECN enantiomer was about 33 times less potent than (+)-ECN, with an IC50 value of 10 mu M and a n amount of maximal block comparable to (+)-ECN. (+)-ECN was less effe ctive at blocking high-voltage-activated Ca2+ current in DRG neurons ( IC50 value of 9.3 mu M with maximal block of about 27%) and hippocampa l neurons. (+)-ECN (10 mu M) had minimal effects on voltage-gated sodi um and potassium currents in rat chromaffin cells. The results identif y a steroid with no effects on GABA receptors that produces a partial inhibition of T-type Ca2+ current with reasonably high affinity and se lectivity. Further study of steroid actions on T currents may lead to even more selective and potent agents.