己环铵和硅己环铵衍生物与毒蕈碱受体亚型的结合及功能特性

Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor subtypes.

作者信息

Waelbroeck M, Camus J, Tastenoy M, Feifel R, Mutschler E, Tacke R, Strohmann C, Rafeiner K, Rodrigues de Miranda J F, Lambrecht G

机构信息

Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Belgium.

出版信息

Br J Pharmacol. 1994 Jun;112(2):505-14. doi: 10.1111/j.1476-5381.1994.tb13102.x.

DOI:10.1111/j.1476-5381.1994.tb13102.x

PMID:8075869

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1910350/

Abstract

We have compared the binding properties of several hexocyclium and sila-hexocyclium derivatives to muscarinic M1 receptors (in rat brain, human neuroblastoma (NB-OK 1) cells and calf superior cervical ganglia), rat heart M2 receptors, rat pancreas M3 receptors and M4 receptors in rat striatum, with their functional antimuscarinic properties in rabbit vas deferens (M1/M4-like), guinea-pig atria (M2), and guinea-pig ileum (M3) muscarinic receptors. 2. Sila-substitution (C/Si exchange) of hexocyclium (-->sila-hexocyclium) and demethyl-hexocyclium (-->demethyl-sila-hexocyclium) did not significantly affect their affinities for muscarinic receptors. By contrast, sila-substitution of o-methoxy-hexocyclium increased its affinity 2 to 3 fold for all the muscarinic receptor subtypes studied. 3. The p-fluoro- and p-chloro-derivatives of sila-hexocyclium had lower affinities than the parent compound at the four receptor subtypes, in binding and pharmacological studies. 4. In binding studies, o-methoxy-sila-hexocyclium (M1 = M4 > or = M3 > or = M2) had a much lower affinity than sila-hexocyclium for the four receptor subtypes, and discriminated the receptor subtypes more poorly than sila-hexocyclium (M1 = M3 > M4 > M2). This is in marked contrast with the very clear selectivity of o-methoxy-sila-hexocyclium for the prejunctional M1/M4-like heteroreceptors in rabbit vas deferens. 5. The tertiary amines demethyl-hexocyclium, demethyl-sila-hexocyclium and demethyl-o-methoxy-sila-hexocyclium had 10 to 30 fold lower affinities than the corresponding quaternary ammonium derivatives.

摘要

我们比较了几种己环铵和硅己环铵衍生物与毒蕈碱M1受体（在大鼠脑、人神经母细胞瘤（NB-OK 1）细胞和小牛颈上神经节中）、大鼠心脏M2受体、大鼠胰腺M3受体以及大鼠纹状体中的M4受体的结合特性，以及它们在兔输精管（M1/M4样）、豚鼠心房（M2）和豚鼠回肠（M3）毒蕈碱受体中的抗毒蕈碱功能特性。2. 己环铵（→硅己环铵）和去甲基己环铵（→去甲基硅己环铵）的硅取代（碳/硅交换）对它们与毒蕈碱受体的亲和力没有显著影响。相比之下，邻甲氧基己环铵的硅取代使其对所有研究的毒蕈碱受体亚型的亲和力增加了2至3倍。3. 在结合和药理学研究中，硅己环铵的对氟和对氯衍生物在四种受体亚型上的亲和力低于母体化合物。4. 在结合研究中，邻甲氧基硅己环铵（M1 = M4 ≥ M3 ≥ M2）对四种受体亚型的亲和力远低于硅己环铵，并且比对硅己环铵（M1 = M3 > M4 > M2）更难以区分受体亚型。这与邻甲氧基硅己环铵对兔输精管中突触前M1/M4样异源受体具有非常明确的选择性形成鲜明对比。5. 叔胺去甲基己环铵、去甲基硅己环铵和去甲基邻甲氧基硅己环铵的亲和力比相应的季铵衍生物低10至30倍。