ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P575

Novel potent and selective non-peptide ligands of ghrelin receptor: characterization of endocrine and extraendocrine actions

Antonio Torsello1, Elena Bresciani1, Aline Moulin2, Laura Tamiazzo1, Ilaria Bulgarelli1, Simona Caporali1, Jean-Alain Fehrentz2, Jean Martinez2, Daniel Perrissoud3 & Vittorio Locatelli1

1Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy; 2UMR 5247, Institute of Biomolecules Max Mousseron (IBMM), Faculté de Pharmacie, Université Montpellier 1, Montpellier, France; 3Aeterna Zentaris, Frankfurt, Germany.

Several synthetic peptide and non-peptide ligands of the GHS-R1a have been described that release GH and stimulate food intake. Starting from a triazole scaffold, we have designed and prepared novel small molecules with high binding affinity to the GHS-R1a and we have investigated their effects in vitro on free intracellular calcium levels and in vivo on food intake and GH secretion in the rat. In CHO cells transfected with the GHS-R1a, hexarelin stimulated calcium levels in a concentration-dependent fashion. Hexarelin is a well characterized hexapeptide that was used as positive control. The compounds JMV2810, JMV3012 and JMV3021 given alone stimulated intracellular calcium levels, but in combination with hexarelin significantly inhibited its stimulatory effects. The GH stimulating activity of the compounds was studied in 10-day old rats, a model previously validated in our lab. Hexarelin, JMV2951, JMV3012 and JMV3021 significantly stimulated GH secretion. Given in association with hexarelin, JMV2951 blunted its GH-releasing effects, whereas JMV2810, JMV3012 and JMV3021 did not modify hexarelin activity. In young-adult rats, hexarelin effectively stimulated feeding behaviour. JMV2951 also stimulated food intake, whereas JMV2810, JMV3012 and JMV3021 had no effects. Interestingly, JMV2951 given in combination with hexarelin did not modify the stimulation of food intake induced by the latter, whereas JMV2810, JMV3012 and JMV3021 significantly inhibited hexarelin effects on feeding behaviour. In conclusion our results show that novel triazole agonists of the GHS-R1a might be endowed with effects on GH secretion divorced from those on feeding behaviour, further supporting the hypothesis that several receptors or signalling pathways might be involved. JMV2951, a potent GHS-R1a agonist stimulating both food intake and GH secretion, has been selected for further characterization of its effects in a rat cisplatin-induced cachexia model.