Synthesis and Pharmacological in Vitro and in Vivo Evaluations of Novel Triazole Derivatives as Ligands of the Ghrelin Receptor. 1

Abstract

A new series of growth hormone secretagogue (GHS) analogues based on the 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and their ability to stimulate intracellular calcium release to the cloned hGHS-1a ghrelin receptor expressed in LLC PK-1 cells. We have synthesized potent ligands of this receptor, some of them behaving as agonists, partial agonists, or antagonists. Some compounds among the most potent, i.e., agonist 29c (JMV2873), partial agonists including 21b (JMV2810), antagonists 19b (JMV2866) and 19c (JMV2844), were evaluated for their in vivo activity on food intake, after sc injection in rodents. Some compounds were found to stimulate food intake like hexarelin; some others were identified as potent hexarelin antagonists in this assay. Among the tested compounds, 21b was identified as an in vitro ghrelin receptor partial agonist, as well as a potent in vivo antagonist of hexarelin-stimulated food intake in rodents. Compound 21b was without effect on GH release from rat. However, in this series of compounds, it was not possible to find a clear correlation between in vitro and in vivo results.

Pharmacological significance of triazole scaffold

“…Some compounds showed Ghrelin receptor agonistic activity and enhanced the release of growth hormone in the growth hormone deficient patients [78]. …”

Therapy for Obesity Based on Gastrointestinal Hormones

“…However, some data indicate an impaired growth hormone axis in the ghrelin receptor knock-out mice, a finding that raises some concern. Although, preclinical studies with agonists, and antagonists, to the growth hormone secretagogue receptor indicate that it is possible to distinguish between the actions of ghrelin on growth hormone secretion and food intake [104,105]. These findings indicate that the effects on food intake might be facilitated through an alternative receptor to the well-known growth hormone secretagogue receptor, thus opening the opportunity to develop specific drugs.…”

Structure–Activity Analysis of the Growth Hormone Secretagogue GHRP‐6 by α‐ and β‐Amino γ‐Lactam Positional Scanning

“…Chem Biol Drug Des 2010; 75: [40][41][42][43][44][45][46][47][48][49][50](S)-amino lactam analogs on both GHS-R1a and CD36 were determined (32).…”