New galanin(1-15) analogues modified in positions 9, 10 and 11 act as galanin antagonists on glucose-induced insulin secretion.

Galanin (GAL) is a 29-amino-acid residue peptide originally isolated from porcine upper small intestine. GAL exhibits various physiological activities, such as effects on hormones release, smooth muscles contractions, gastric acid secretion, neurons degeneration and feeding. One of the biological actions of GAL is the inhibition of insulin secretion from the pancreatic beta-cells. In our studies we have designed several new 15-amino-acid-residue galanin fragment analogues modified in positions: 6, 8, 9, 10, 11 and tested for their effects on glucose-induced insulin secretion from isolated rat pancreatic islets of Langerhans. In vitro insulin secretion was studied during static incubation. All peptides were tested at two concentrations: 0.1 microM and 1 microM. Among the analogues derived from GAL(1-15)NH(2) peptide: [Phe(9)]GAL(1-15)NH(2) and [Pro(11)]GAL(1-15)NH(2) were found to be the potent antagonists against the inhibitory effect of GAL on glucose-induced insulin secretion from the isolated rat pancreas. These analogues block the GAL-mediated inhibition of insulin secretion. The present studies have shown that analogues: [Phe(9)]GAL(1-15)NH(2) and [Pro(11)]GAL(1-15)NH(2) may be a key compounds for developing a more potent GAL antagonists.

Synthesis and biological properties of new chimeric galanin analogue GAL(1-13)-[Ala10,11]ET-1(6-21)-NH2.

Several chimeric peptides consisting of the N-terminal fragment of galanin (GAL) and C-terminal fragments of other bioactive peptides (e.g. substance P, bradykinin, neuropeptide Y, mastoparan) have been synthesized and reported as high-affinity galanin receptor antagonists. Recently we have synthesized a new chimeric peptide, GAL(1-13)-[Ala(10,11)]ET-1(6-21)-NH(2), consisting of the N-terminal fragment of GAL and the C-terminal fragment of endothelin-1 (ET-1) analogue. This chimera was previously shown to be a moderate-affinity ligand to hypothalamic galanin receptors with a K(D) value of 205 nM. However, its biological action has been unknown so far. In our studies we characterized the biological properties of this new chimeric analogue, investigating its action on rat isolated gastric smooth muscles and influence on insulin secretion from rat isolated islets of Langerhans. Data acquired in the course of our studies suggest that analogue GAL(1-13)-[Ala(10,11)]ET-1(6-21)-NH(2) does not seem to be a potent galanin receptor antagonist in the gastrointestinal tract.