SAR and QSAR studies on the N-terminally acylated pentapeptide agonists for GPR54.
Kisspeptins (KPs) play important roles in the regulation of physiological and pathological states through activation of the cognate receptor GPR54. Our previous studies to downsize KP agonists to the essential GPR54 pharmacophore identified peptides 1-3 as low molecular weight GPR54 agonists. In this study, the effect of N-terminal acyl groups on the activity of a series of analogues (R-Phe-Gly-Leu-Arg-Trp-NH2) was investigated in order to develop novel potent GPR54 agonists. Among the compounds developed, the most potent agonistic activity for GPR54 was observed for N-terminal 4-fluorobenzoyl analogue 29. Using quantitative structure-activity relationship studies, it was demonstrated that the inductively negative and small substituents were preferred at the 4-position of N-terminal benzoyl groups.
Tomita
Kenji
K
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Oishi
Shinya
S
Cluzeau
Jérôme
J
Ohno
Hiroaki
H
Navenot
Jean-Marc
JM
Wang
Zi-xuan
ZX
Peiper
Stephen C
SC
Akamatsu
Miki
M
Fujii
Nobutaka
N
D000215:Acylation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008958:Models, Molecular; D009842:Oligopeptides / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000074502:Receptors, Kisspeptin-1; D013329:Structure-Activity Relationship
C118688:KISS1R protein, human; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1