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Vol. 54, Issue 5, 918-927, November 1998

Enantioselective Blockade of T-type Ca2+ Current in Adult Rat Sensory Neurons by a Steroid That Lacks gamma -Aminobutyric Acid-Modulatory Activity

Slobodan M. Todorovic, Murali Prakriya, Yasunori M. Nakashima,1 Kent R. Nilsson, Mingchen Han, Charles F. Zorumski, Douglas F. Covey, and Christopher J. Lingle

Department of Anesthesiology (S.M.T., M.P., Y.M.N.,C.J.L.), Department of Molecular Biology and Pharmacology (K.R.N., M.H., D.F.C.), and Department of Psychiatry (C.F.Z.), Washington University School of Medicine, St. Louis, Missouri 63110

A number of steroids seem to have anesthetic effects resulting primarily from their ability to potentiate currents gated by gamma -aminobutyric acidA (GABAA) receptor activation. One such compound is (3alpha ,5alpha ,17beta )-3-hydroxyandrostane-17-carbonitrile [(+)-ACN]. We were interested in whether carbonitrile substitution at other ring positions might result in other pharmacological consequences. Here we examine effects of (3beta ,5alpha ,17beta )-17-hydroxyestrane-3-carbonitrile [(+)-ECN] on GABAA receptors and Ca2+ channels. In contrast to (+)-ACN, (+)-ECN does not potentiate GABAA-receptor activated currents, nor does it directly gate GABAA-receptor mediated currents. However, both steroids produce an enantioselective reduction of T-type current. (+)-ECN blocked T current with an IC50 value of 0.3 µM with a maximal block of 41%. (+)-ACN produced a partial block of T current (44% maximal block) with an IC50 value of 0.4 µM. Block of T current showed mild use- and voltage-dependence. The (-)-ECN enantiomer was about 33 times less potent than (+)-ECN, with an IC50 value of 10 µM and an amount of maximal block comparable to (+)-ECN. (+)-ECN was less effective at blocking high-voltage-activated Ca2+ current in DRG neurons (IC50 value of 9.3 µM with maximal block of about 27%) and hippocampal neurons. (+)-ECN (10 µM) had minimal effects on voltage-gated sodium and potassium currents in rat chromaffin cells. The results identify a steroid with no effects on GABAA receptors that produces a partial inhibition of T-type Ca2+ current with reasonably high affinity and selectivity. Further study of steroid actions on T currents may lead to even more selective and potent agents.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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