Todorovic S M, Prakriya M, Nakashima Y M, Nilsson K R, Han M, Zorumski C F, Covey D F, Lingle C J
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mol Pharmacol. 1998 Nov;54(5):918-27. doi: 10.1124/mol.54.5.918.
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.
许多类固醇似乎具有麻醉作用，这主要源于它们增强由γ-氨基丁酸A（GABAA）受体激活所介导电流的能力。一种这样的化合物是(3α,5α,17β)-3-羟基雄甾烷-17-腈[(+)-ACN]。我们感兴趣的是在其他环位置进行腈取代是否会导致其他药理结果。在此，我们研究(3β,5α,17β)-17-羟基雌甾烷-3-腈[(+)-ECN]对GABAA受体和Ca2+通道的影响。与(+)-ACN不同，(+)-ECN不会增强GABAA受体激活的电流，也不会直接控制GABAA受体介导的电流。然而，这两种类固醇都能对T型电流产生对映体选择性的抑制作用。(+)-ECN以0.3微摩尔的半数抑制浓度（IC50）阻断T电流，最大阻断率为41%。(+)-ACN以0.4微摩尔的IC50值对T电流产生部分阻断（最大阻断率44%）。T电流的阻断表现出轻度的使用和电压依赖性。(-)-ECN对映体的效力比(+)-ECN低约33倍，IC50值为10微摩尔，最大阻断量与(+)-ECN相当。(+)-ECN在阻断背根神经节（DRG）神经元和海马神经元中的高压激活Ca2+电流方面效果较差（IC50值为9.3微摩尔，最大阻断率约为27%）。(+)-ECN（10微摩尔）对大鼠嗜铬细胞中的电压门控钠电流和钾电流影响极小。这些结果确定了一种对GABAA受体无作用，但能以相当高的亲和力和选择性对T型Ca2+电流产生部分抑制作用的类固醇。对类固醇对T电流作用的进一步研究可能会产生更具选择性和效力的药物。
