Selective agonists for substance P and neurokinin receptors

Abstract

A series of neurokinin analogues and fragments have been prepared in an attempt to identify selective agonists for NK-P, NK-A and NK-B receptors. The compounds have been tested on the dog carotid artery (NK-P receptor system), the rabbit pulmonary artery (NK-A) and the rat portal vein (NK-B). C-terminal substituted analogues of the three neurokinins have provided indication that NK-P receptor selectivity is improved by the oxidation of methionine to Met(O2), while selectivity for NK-A is favoured by replacing Met with NIe. Selectivity for NK-P receptors is further improved by the replacement of Gly9 with Sar. Selectivity and affinity for NK-B receptors is markedly increased when Val7 is replaced with MePhe in both the fragment NKB (4-10) and NKB. The results of the present study indicate that a) [Sar9,Met(O2)11]SP is a potent and selective agonist for the NK-P receptors of the dog carotid artery; b) [MePhe7]NKB is a very potent and selective stimulant of receptors for neurokinin B and c) [Nle10]NKA (4-10) is a promising compound, showing some selectivity for NK-A receptor; further modifications are however needed to improve its affinity.