Galanin, galantide and galanin(1-14)-[alpha-aminobutyric acid(8)]-scyliorhinin-I: Structure dependent effects on the rat isolated gastric fundus

The study was undertaken using selected pharmacodynamic parameters to describe the effects of porcine galanin(1-29)-NH2; porcine galanin fragments; galantide; porcine galanin(1-14)-[alpha-aminobutyric acid(8)]scyliorhinin-I and the analogues of the latter peptides on rat isolated gastric fundus muscle. All tested peptides, apart from galanin(16-29)-NH2 evoked reproducible concentration-dependent contractions with significantly decreased activities in comparison to the potency of the native galanin(1-29)-NH2 molecule. The order of the contractile ability in the group of galanin(1-29)-NH2 short fragments was as follows: [lysine(14)]galanin(1-15)-NH2>galanin(1-15)-OH>galanin(1-15)-NH2>[glycine(5)] galanin(1-15)-NH2>galanin(2-15)-NH2>[glycine(5),lysine(14)]galanin(1-15)-NH2. Aside from [lysine(14)]galanin(1-15)-NH2 which had a lower efficacy, none of the peptides showed significant changes in this respect in comparison to the intact galanin(1-29)-NH2 molecule. The concentration-response curves of the tested peptides were to the right and their slopes besides from: galanin(1-15)-OH; galanin(2-15)-NH2; [glycine(5)]galanin(1-15)-NH2 remained not significantly different from galanin(1-29)-NH2. Hill's coefficient for galanin(1-29)-NH2 is 1.03 indicating an interaction of one galanin(1-29)-NH2 molecule with one receptor, fulfilling criteria of classical receptor theory. For galanin fragments Hill's coefficients are <1 implying that the rules of classical theory may not apply. Galantide and analogues exhibited a subsequent decrease in potency: [cycloleucine(4)] galantide>galantide>[homoserine(6)]galantide>[phenylalnine(4fluor)(17)]galantide. Galanin(1-14)-[alpha-aminobutyric acids]-scyliorhinin-I and its analogues contracted the gastric fundus with a decline in strength: galanin(1-13)-[norleucine(10)]-scyliorhinin-I(3-10)>galanin(1-13)-[phenylalanine(4fluor)(7)]-scyliorhinin-I>galanin(1-14)-[alpha-aminobutyric acid(8)]-scyliorhinin-I>galanin(1-13)-[alpha-aminobutyric acid(8), norleucine(10)]-scyliorhinin-I(3-10). They all displayed a greater efficacy than galanin(1-29)-NH2, and the concentration-response curves were slightly to the right, almost parallel to that of galanin(1-29)-NH2. Slopes of the curves were not significantly different from galanin(1-29)-NH2. Hill's coefficient for the galantide, [cycloleucine(4)]galantide; [homoserine(6)] galantide; [phenylalanine(4fluor)(17)]galantide and galanin(1-13)-[phenylalanine(4fluor)(7)]-scyliorhinin-I are <1. Hill's coefficients for galanin(1-13)-[norleucine(10)]-scyliorhinin-I(3-10); galanin(1-14)[alpha-aminobutyric acid(8)]-scyliorhinin-I; galanin(1-14)-[alpha-aminobutyric acids, norleucine(10)]scyIiorhinin-I(3-10) are >1. A Hill's coefficient markedly different from 1 might indicate that an activation of more than one type of receptors, negative or positive receptor cooperativity or multiple-step agonist-receptor reaction. (C) 1997 The Italian Pharmacological Society.