Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. 1.
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.
Demange
Luc
L
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS-Universités Montpellier I et II, BP. 14491, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
Boeglin
Damien
D
Moulin
Aline
A
Mousseaux
Delphine
D
Ryan
Joanne
J
Bergé
Gilbert
G
Gagne
Didier
D
Heitz
Annie
A
Perrissoud
Daniel
D
Locatelli
Vittorio
V
Torsello
Antonio
A
Galleyrand
Jean-Claude
JC
Fehrentz
Jean-Alain
JA
Martinez
Jean
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D004435:Eating / Q000187:drug effects; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*; D054440:Receptors, Ghrelin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D014230:Triazoles; D013006:Growth Hormone; D002118:Calcium