CHARACTERIZATION OF TACHYKININ NK2 RECEPTOR ON DOG PROXIMAL COLON - ANTAGONISM BY MEN-10,627 AND SR-48,968

The nature of the tachykinin receptors involved in the contraction of the circular muscle of dog colon has been investigated. The following rank order of potency for agonists was obtained: [Sar(9),Met(O-2)(11)] substance P greater than or equal to neurokinin A > [beta-Ala(8)]neuro kinin A-(4-10) much greater than [MePhe(7)]neurokinin B. The efficacy of the tachykinin NK2 receptor agonists was significantly greater than that of the tachykinin NK1 receptor agonists and of carbachol. A conc entration-dependent rightward shift of the motor response to neurokini n A (obtained in the presence of (+/-)-CP 96,345) was induced by pepti de and non-peptide tachykinin NK2 receptor antagonists with this rank order: MEN 10,627 = SR 48,968 much greater than L 659,877 > MEN 10,376 > MDL 28,564. MEN 10,627 and SR 48,968 affinities were similar to tho se measured in human tissues. In conclusion, the tachykinin NK1 2 rece ptor plays a predominant role in tachykinin-induced contraction of the canine colonic circular muscle and this tissue could be useful to pre dict the pharmacological actions of MEN 10,627 and SR 48,968 in human colon.