CHARACTERIZATION OF BIBN-99 - A LIPOPHILIC AND SELECTIVE MUSCARINIC M(2)-RECEPTOR ANTAGONIST

被引：34

作者：

DOODS, H ^{[1
]}

ENTZEROTH, M ^{[1
]}

ZIEGLER, H ^{[1
]}

SCHIAVI, G ^{[1
]}

ENGEL, W ^{[1
]}

MIHM, G ^{[1
]}

RUDOLF, K ^{[1
]}

EBERLEIN, W ^{[1
]}

机构：

[1] BOEHRINGER INGELHEIM ITALIA SPA,I-20130 MILAN,ITALY

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 1993年 / 242卷 / 01期

关键词：

BIBN-99; MUSCARINIC M(2)-RECEPTOR ANTAGONIST; MUSCARINIC RECEPTORS (M(1)-M(3); M1-M5); AF-DX-116;

D O I：

10.1016/0014-2999(93)90005-3

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The present study was designed to characterize the receptor selectivity profile of the novel muscarinic M2 receptor antagonist BIBN 99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-][1,4]benzodiazepin-6-one). In radioligand binding studies BIBN 99 showed high affinity for m2/M2 sites (pK(i) = 7.52/7.57), intermediate affinity for m4 sites (pK(i) = 6.76) and low affinity for ml/M1 (pK(i) = 5.97/6.17), m3/M3 (pK(i) = 6.11/6.04) and m5 sites (pK(i) = 5.84). Functional studies in vitro showed BIBN 99 to be a competitive antagonist and to have an 11- to 25-fold higher affinity for M2 receptors than for putative M1 receptors in the rabbit vas deferens or M3 receptors in guinea-pig trachea. In vivo studies revealed that BIBN 99 is able to cross the blood-brain barrier, and although showing an approximately 3-fold higher affinity for M2 binding sites BIBN 99 appeared to be 7- to 18-fold less potent than AF-DX 116 in inhibiting muscarinic agonist or vagally induced bradycardia in rats and guinea-pigs. The results show that BIBN 99 is the first lipophilic muscarinic M2 receptor antagonist to have remarkable M2 versus M1 selectivity (30-fold). In addition, BIBN 99 possesses central nervous system activity and only minor peripheral cardiac effects.

引用

页码：23 / 30

页数：8

共 36 条

[1] THE CARDIOSELECTIVITY OF HIMBACINE - A MUSCARINE RECEPTOR ANTAGONIST [J].