Geometry and charge determine pharmacological effects of steroids on <i>N</i>-methyl-D-aspartate receptor-induced Ca<SUP>2+</SUP> accumulation and cell death

作     者：Weaver, CE Land, MB Purdy, RH Richards, KG Gibbs, TT Farb, DH 

作者机构：Boston Univ Sch Med Dept Pharmacol Mol Neurobiol Lab Boston MA 02118 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第293卷第3期

页      面：747-754页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：NIMH NIH HHS [MH-49469] Funding Source: Medline 

主　　题：钙/代谢 细胞死亡/药物作用 海马/药物作用 分子构象 N-甲基天冬氨酸/毒性 大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/药物作用 受体 N-甲基-D-天冬氨酸/生理学 甾类/药理学 构效关系 动物 大鼠 

摘      要：Modulation of N-methyl-D-aspartate (NMDA) receptor function by a series of sulfated steroids and dicarboxylic acid ester analogs of pregnenolone sulfate and pregnanolone sulfate was investigated in cultured hippocampal neurons. The bent steroid ring structure associated with 5 beta-stereochemistry favors receptor inhibition, whereas the more planar ring structure of the pregn-5-enes and 5 alpha-pregnanes favors potentiation of NMDA-induced [Ca2+] increases and neuronal cell death. The nature of the negatively charged group attached to the steroid C3 position is important for both the neuroprotection afforded by pregnane steroids and the exacerbation of NMDA-induced neuronal death by pregn-5-enes. Dicarboxylic acid hemiesters of various lengths can substitute for the sulfate group of the positive modulator pregnenolone sulfate and the negative modulator pregnanolone sulfate. This result suggests that precise coordination with the oxygen atoms of the sulfate group is not critical for modulation and that the steroid recognition sites can accommodate bulky substituents at C3. The capacity of charged steroids to enhance or protect against NMDA-induced death of hippocampal neurons is strongly correlated with modulation of NMDA-induced Ca2+ accumulation, indicating that direct enhancement or inhibition of NMDA receptor function is responsible for the proexcitotoxic or neuroprotective effects of these steroids.