DIFFERENT MECHANISM OF TACHYKININ NK2 RECEPTOR BLOCKADE BY SR-48968 AND MEN-10,627 IN THE GUINEA-PIG ISOLATED GALLBLADDER AND COLON

Citation
R. Patacchini et al., DIFFERENT MECHANISM OF TACHYKININ NK2 RECEPTOR BLOCKADE BY SR-48968 AND MEN-10,627 IN THE GUINEA-PIG ISOLATED GALLBLADDER AND COLON, European journal of pharmacology, 271(1), 1994, pp. 111-119
Citations number
26
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00142999
Volume
271
Issue
1
Year of publication
1994
Pages
111 - 119
Database
ISI
SICI code
0014-2999(1994)271:1<111:DMOTNR>2.0.ZU;2-Z
Abstract
The mechanism of action of the tachykinin NK2 receptor antagonists, SR 48968 S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2- (3,4-dichlor ophenyl)butyl]benzamide) and MEN 10,627 (cyclo[(Met-Asp-Trp-Phe-Dap-Le u) cycle (2 beta-5 beta)]), was compared in the guinea-pig isolated ga llbladder and circular muscle of proximal colon by using neurokinin A and [beta Ala(8)]neurokinin A-(4-10) as agonists. The experiments perf ormed with colon were in the presence of the tachykinin NK2 receptor-s elective antagonist, (+/-)-CP-96,345 henyl)-methyl]-1-azabicyclo[2,2,2 ]octan-3-amine]). SR 48968 caused an insurmountable antagonism of tach ykinin NK2 receptor-mediated contraction in both preparations; its blo ckade was essentially irreversible, since it was not reversed by washo ut (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. In contrast, MEN 10,627 produced simple competitive antago nism, which was time-independent and fully reversible in both preparat ions. In both preparations, the simultaneous administration of SR 4896 8 and MEN 10,627 produced an intermediate antagonism of the responses to the agonists, as compared to the antagonism produced by each antago nist alone. The present results are discussed in the light of the repo rted interaction of SR 48968 with tachykinin NK2 receptors at a recogn ition epitope distinct from that of agonist(s).