Potent and selective MC-4 receptor agonists based on a novel disulfide scaffold.
Extensive structure-activity relationship studies utilizing a beta-MSH-derived cyclic nonapeptide, Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (3), led to identification of a series of novel MC-4R selective disulfide-constrained hexapeptide analogs including Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (12). The structural modifications associated with profound influence on MC-4R potency and selectivity were ring size, ring conformation, and the aromatic substitution of the D-Phe7. These cyclic peptide analogs provide novel and enhanced reagents for use in the elucidation of melanocortin-4 receptor-related physiology, and may additionally find application in the treatment of obesity and related metabolic disorders.
Yan
Liang Z
LZ
Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. lyan@lilly.com
Flora
David
D
Edwards
Patrick
P
Smiley
David L
DL
Emmerson
Paul J
PJ
Hsiung
Hansen M
HM
Gadski
Robert
R
Hertel
JeAnne
J
Heiman
Mark L
ML
Husain
Saba
S
O'Brien
Thomas P
TP
Kahl
Steven D
SD
Zhang
Lianshan
L
Dimarchi
Richard D
RD
Mayer
John P
JP
D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000737:chemistry*; D013058:Mass Spectrometry; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
D004220:Disulfides; D044105:Receptor, Melanocortin, Type 4