Structure-activity relationship of linear tetrapeptides Tic-DPhe-Arg-Trp-NH2 at the human melanocortin-4 receptor and effects on feeding behaviors in rat.
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. zhixiong_ye@merck.com
Zhixiong
Z
Ye
Tanya
T
MacNeil
David H
DH
Weinberg
Rubana N
RN
Kalyani
Rui
R
Tang
Alison M
AM
Strack
Beth A
BA
Murphy
Ralph T
RT
Mosley
D
D
Euan MacIntyre
Lex H T
LH
Van der Ploeg
Arthur A
AA
Patchett
Matthew J
MJ
Wyvratt
Ravi P
RP
Nargund
D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009842:Oligopeptides / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001067:Appetite Depressants; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4