Sialogogic activity in the rat of peptides analogous to [Tyr8]-substance P in which substitutions have been made in the N-terminal amino acids

In order to elucidate the regulatory roles for salivation of amino acids in positions 1–4 of the N-terminal region of [Tyr8]-substance P (SP), the structure–sialogogic activity correlations of various synthetic octa- to undecapeptides replaced in positions 1–4 of [Tyr8]-SP with each of 19 common amino acids, one by one, and with the same sequence of the C-terminal heptapeptide as that of [Tyr8]-SP, were studied in the submandibular glands of rats after intraperitoneal injection. Each of 19 octa-, nona-, deca- and undecapeptides with replaced amino acids and a penta- to decapeptide with the progressive elimination of the N-terminal portion were newly synthesized by the multipin peptide method. All octa- to undecapeptides replaced with each of 19 common amino acids in positions 1–4 had sialogogic activities. In 19 octa- and decapeptides in which P4 and P2 had been replaced, four and three replacements, respectively, had significantly increased secretory activities. In contrast, in 19 nonapeptides in which K3 had been replaced, none had significantly increased secretory activities. Furthermore, in 19 undecapeptides in which R1 had been replaced, most replacements had significantly increased or equipotent activities for fluid secretion. It is concluded that amino acids in the N-terminal region of various tachykinins may not need to be strictly conserved and that amino acid residues in the N-terminal portion, R1 in particular and P2, may strongly inhibit secretory activity.