Pharmacological characterization of four related substance P antagonists.

Abstract

The purpose of this pharmacological study was to further characterize 4 related substance P (SP) analogues, namely (D‐Pro2, D‐Phe7, D‐Trp9)‐SP (I), (D‐Pro2, D‐Trp7.9)‐SP (II), (D‐Arg1, D‐Pro2, D‐Phe7, D‐Trp9)‐SP (III) and (D‐Arg1, D‐Pro2, D‐Trp7.9)‐SP (IV). At a concentration of 10‐4 M they were found to have little or no smooth muscle‐contracting effect on the guinea‐pig ileum, analogues I and II having substantially less agonist activity than III and IV. Pretreatment with the analogues inhibited the contractile responses to SP, but not to histamine or acetylcholine. Of the 4 analogues, II was found to be the most potent SP antagonist. The contractile responses to physalaemin and eledoisin were also inhibited by analogue II. The concentration‐response curves for SP were shifted in parallel to higher concentrations in the presence of the analogues. The pA2‐values derived from Schild plots were 4.61 for (I), 5.43 for (II), 4.69 for (III) and 5.11 for (IV). Except for (I) the slopes of the regression lines of the Schild plots were close to unity. The data are consistent with simple competitive antagonism over the concentration ranges investigated. Without being secretagogues per se, the analogues inhibited SP‐stimulated salivary secretion in the rat. Physalaemin‐stimulated secretion was inhibited by analogue II. The inhibitory effect of sequences with D‐Arg1 instead of L‐Arg1 seemed to be of longer duration. Not one of these analogues blocked the blood pressure‐lowering effect of SP, which indicates the existence of more than one type of SP receptor. This study has shown that 4 related SP analogues specifically inhibit the actions of SP and structurally related peptides physalaemin and eledoisin, both in vitro and in vivo. Analogues II‐IV seem to inhibit in a simple competitive manner. (D‐Pro2, D‐Trp7.9)‐SP was the most potent of the 4 SP antagonists.