The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist.
Ghrelin is a 28-residue peptide acylated with an n-octanoyl group on the Ser 3 residue, predominantly produced by the stomach. Ghrelin displays strong growth hormone (GH) releasing activity, which is mediated by the activation of the so-called GH secretagogue receptor type 1a (GHS-R1a). Given the wide spectrum of biological activities of Ghrelin in neuroendocrine and metabolic pathways, many research groups, including our group, developed synthetic peptide, and nonpeptide GHS-R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists. In this highlight article, we will focus on the discovery of a GHS-R1a antagonist compound, JMV 2959, which has been extensively studied in different in vitro and in vivo models. We will first describe the peptidomimetic approach that led us to discover this compound. Then we will review the results obtained with this compound in different studies in the fields of food intake and obesity, addictive behaviors, hyperactivity and retinopathy.
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Universités Montpellier 1 Montpellier 2, Montpellier, France.
Aline
A
Moulin
Luc
L
Brunel
Damien
D
Boeglin
Luc
L
Demange
Johanne
J
Ryan
Céline
C
M'Kadmi
Séverine
S
Denoyelle
Jean
J
Martinez
Jean-Alain
JA
Fehrentz
D000818:Animals; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; C569751:N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide; D054440:Receptors, Ghrelin; D014230:Triazoles; C045575:1,2,4-triazole; D005998:Glycine