Enantioselective blockade of T-type Ca2+ current in adult rat sensory neurons by a steroid that lacks gamma-aminobutyric acid-modulatory activity.
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 microM with a maximal block of 41%. (+)-ACN produced a partial block of T current (44% maximal block) with an IC50 value of 0.4 microM. 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 microM 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 microM with maximal block of about 27%) and hippocampal neurons. (+)-ECN (10 microM) 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.
Todorovic
S M
SM
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Prakriya
M
M
Nakashima
Y M
YM
Nilsson
K R
KR
Han
M
M
Zorumski
C F
CF
Covey
D F
DF
Lingle
C J
CJ
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000145:classification / Q000502:physiology*; D019439:Chromaffin Cells / Q000187:drug effects / Q000502:physiology; D004962:Estranes / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology; D011277:Pregnanediones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D013237:Stereoisomerism
C115894:17-hydroxyestrane-3-carbonitrile; D000777:Anesthetics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004962:Estranes; D018757:GABA Modulators; D009570:Nitriles; D015221:Potassium Channels; D011277:Pregnanediones; D011963:Receptors, GABA-A; D015222:Sodium Channels; C084683:3-hydroxy-5-estrane-17-carbonitrile; C006477:alphaxalone