Structure–activity studies on substance P

Abstract

A complete series of analogues of substance P (SP) in which L-Ala was used to replace the natural residues one by one, and the C-terminal free acid SP, were synthesized and tested in order to study the relationships between chemical structure and biological activities. All compounds were tested for their hypotensive effect on the rat blood pressure and for their myotropic activities on the guinea pig ileum, the rabbit anterior mesenteric vein, and the rat vas deferens.The results indicate that the first five residues from the amino end and Gly⁹ can be replaced by L-Ala without change of hypotensive or myotropic activities, but the substitution of the residues from the carboxyl end (Met¹¹, Leu¹⁰, Phe⁸, and Phe⁷) with L-Ala brings about variable losses of affinity. All analogues maintain full intrinsic activity in the guinea pig ileum; [Ala¹⁰]-SP and [Ala¹¹]-SP maintain more than 80% of intrinsic activity in the mesenteric vein, the other analogues being full agonists; moreover, [Ala⁷]-SP and [Ala ⁸]-SP show a weaker hypotensive potency than all other compounds. The effect of SP is not modified by an inhibitor of the converting enzyme (YS 980), but that of SP free acid is either potentiated (rabbit mesenteric vein, rat vas deferens) or not modified (rat blood pressure, guinea pig ileum).The findings presented in this paper are discussed in terms of structure–activity relationships. However, no clear indication has emerged as to the identity of the active group(s) or on a possible distinction between the molecular sequences or groups involved in binding or in stimulation of receptors by SP.