N-苄基取代曲美托喹啉类似物的β-肾上腺素能受体激动剂特性的药理学评价

Pharmacological evaluation of the beta-adrenoceptor agonist properties of N-benzyl substituted trimetoquinol analogues.

作者信息

Shams G, Harrold M W, Grazyl B, Miller D D, Feller D R

机构信息

Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.

出版信息

Eur J Pharmacol. 1990 Aug 10;184(2-3):251-6. doi: 10.1016/0014-2999(90)90616-e.

DOI:10.1016/0014-2999(90)90616-e

PMID:1981872

Abstract

The beta 1- and beta 2-adrenoceptor agonist properties of trimetoquinol (TMQ, I) and N-benzyl ring substituted TMQ analogues (II, 4'-methylbenzylTMQ; III, 4'-chloro-benzylTMQ; IV, 4'-methoxybenzylTMQ; V, 4'-nitrobenzylTMQ; VI, 3',4'-dichlorobenzylTMQ; and VII, 4'-aminobenzylTMQ) were studied in guinea pig atria and trachea. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than VII greater than II greater than V greater than IV greater than VI greater than III and I greater than VII greater than IV = VI greater than V greater than III greater than II, respectively. Whereas the N-benzyl substitution reduced potency for beta-agonist activity, the beta 2/beta 1-selectivity ratio was enhanced by addition of groups to the N-benzyl ring, and the rank order of beta 2-selectivity was VI (10-fold) greater than III (8-fold) = IV (8-fold) greater than VII (3-fold) greater than V = I greater than II. The results show that varying the nature of substituents on the N-benzyl ring of TMQ produces compounds which retain greater beta 2-selectivity.

摘要

在豚鼠心房和气管中研究了曲美托喹（TMQ，I）及N-苄基环取代的TMQ类似物（II，4'-甲基苄基TMQ；III，4'-氯苄基TMQ；IV，4'-甲氧基苄基TMQ；V，4'-硝基苄基TMQ；VI，3'，4'-二氯苄基TMQ；VII，4'-氨基苄基TMQ）的β1-和β2-肾上腺素能受体激动剂特性。所有化合物在心房和气管中均呈现浓度依赖性反应，β-肾上腺素能受体激动剂效力的排序分别为I＞VII＞II＞V＞IV＞VI＞III以及I＞VII＞IV = VI＞V＞III＞II。虽然N-苄基取代降低了β-激动剂活性的效力，但通过在N-苄基环上添加基团提高了β2/β1选择性比值，β2选择性的排序为VI（10倍）＞III（8倍） = IV（8倍）＞VII（3倍）＞V = I＞II。结果表明，改变TMQ的N-苄基环上取代基的性质可产生具有更高β2选择性的化合物。