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
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).