COMPARISON OF NK-2 SELECTIVE PEPTIDE AND NONPEPTIDE ANTAGONISTS IN RAT DISTAL COLON MUSCULARIS MUCOSAE

1 The effects of natural and synthetic tachykinin agonists as well as those of peptide (linear and cyclic) and non-peptide NK-2 antagonists have been assessed in the rat colon muscularis mucosae (RCMM). 2 The rank order of agonist potency was neurokinin A (NKA)>ArgNKB > > Substance P (SP). The selective NK-2 agonist [betaAla8]NKA(4-10) had an intrinsic activity similar to NKA, while [MePhe7]NKB (NK-3 selective) and [Pro9] substance P (SP) sulphone (NK-1 selective) had slight and no motor activity, respectively. 3 All the antagonists produced a concentration-dependent rightward shift of the cumulative concentration-response curve to NKA. The following rank order of affinity was obtained: SR 48968>L659,877>MEN 10376>R396. 4 The antagonism exerted by peptide antagonists (L659,877, MEN 10376 and R396) was unaffected by lengthening of the incubation time or presence of peptidase inhibitors. 5 The pseudopeptide, MDL 28,564, behaved as a weak antagonist. 6 These findings indicate that NK-2 receptors are the main, if not the sole, mediators of tachykinin-induced motor effects in RCMM. The rank order of potency of peptide antagonists, as well as the antagonistic properties of the pseudopeptide MDL 28,564, suggest the existence of preferential expression of NK-2B receptors in RCMM.