Neurokinin receptors antagonists: old and new.

Four neurokinin antagonists of different size have been used to counteract the myotropic effects of substance P, neurokinin A and neurokinin B in isolated organs containing a single receptor type (monoreceptor systems). These are: the dog carotid artery, the rabbit jugular and cava veins and the guinea pig ileum (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3). Undeca and octapeptides containing 2 D-Trp residues in their sequences were slightly more active on the NK-1, than on the NK-2 and NK-3 receptors and showed little selectivity. In contrast, compound AcThr-D.Trp(For)-Phe.NMe Bz was found to be as good an antagonist as the larger compounds and showed some selectivity for the NK-1 receptors. When tested against kinins or angiotensin, all compounds were found to be inactive, suggesting that they are specific for neurokinins. The present results show that NK-1 receptor antagonism can be obtained with compounds of different size, including tripeptides and nonpeptides.