SYNTHESIS AND MUSCARINIC ACTIVITIES OF 1,2,4-THIADIAZOLES

被引：58

作者：

MACLEOD, AM ^{[1
]}

BAKER, R ^{[1
]}

FREEDMAN, SB ^{[1
]}

PATEL, S ^{[1
]}

MERCHANT, KJ ^{[1
]}

ROE, M ^{[1
]}

SAUNDERS, J ^{[1
]}

机构：

[1] MERCK SHARP & DOHME LTD,NEUROSCI RES CTR,DEPT BIOCHEM,HARLOW CM20 2QR,ESSEX,ENGLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1990年 / 33卷 / 07期

关键词：

D O I：

10.1021/jm00169a041

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and l-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [ 3 H] -N-methylscopolamine and [ 3 H]oxotremorine-M. Optimal agonist affinity was observed for 3’-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-05’ bond and the steric requirement of the mono- or bicyclic amine. © 1990, American Chemical Society. All rights reserved.

引用

页码：2052 / 2059

页数：8