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.
Ye
Zhixiong
Z
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. zhixiong_ye@merck.com
MacNeil
Tanya
T
Weinberg
David H
DH
Kalyani
Rubana N
RN
Tang
Rui
R
Strack
Alison M
AM
Murphy
Beth A
BA
Mosley
Ralph T
RT
Euan MacIntyre
D
D
Van der Ploeg
Lex H T
LH
Patchett
Arthur A
AA
Wyvratt
Matthew J
MJ
Nargund
Ravi P
RP
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