Tachykinin antagonists: Substitutions in positions 5 and 6 with amino acids from the primary sequence of substance P homologues

Abstract

A series of tachykinin antagonists has been synthetized by substituting the amino acids of eight naturally occurring tachykinins into the general antagonist [pro 4,trp 7,9,Phe 11]tachykinin-(4–11). Five decapeptide antagonists were also synthetized. These antagonists were tested on four smooth muscle preparations, the rabbit mesenteric vein, the guinea-pig ileum, the guinea-pig trachea and the rat urinary bladder. On all tissues, except the rat urinary bladder, antagonists that had amino acids other than Gln 5Gln 6 found in the substance P molecule were inactive as antagonists, and some had marked intrinsic activity on the guinea-pig ileum and the guinea-pig trachea. The inhibitory activity of these antagonists on the rat urinary bladder, however, was quite marked. The activities of these antagonists on the rat urinary bladder can be summarized as follows: (a) In general decapeptide antagonists were of low affinity. (b) Octapeptide antagonists showed variable affinities against the various tachykinins and some were selective. The only two antagonists which were fairly active against all tachykinins were [pro 4,trp 7,9,Phe 11]SP-(4–11) and [pro 4,trp 7,9,Phe 11] UPE-(4–11). (c) Physalaemin was frequently antagonized in a non-surmountable manner. (d) Eledoisin and kassinin were each inhibited by only one antagonist, and the antagonist was different for each tachykinin. Some tachykinin receptors on smooth muscle have a binding site which is highly selective for Gln 5Gln 6, especially if the affinity of antagonists is considered. Another tissue, the rat urinary bladder, does not exhibit this selectivity. The activity of antagonists at positions 5–6 may need to be considered in evaluating receptor types on smooth muscle.