Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH(2) at the human melanocortin-1 and -4 receptors: histidine substitution.
Systematic substitution of His(6) residue using non-selective hMC4R pentapeptide agonist (Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)) as the template led to the identification of Bu-Atc(6)(2-aminotetraline-2-carboxylic acid)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which showed moderate selectivity towards hMC4R over hMC1R. Further SAR studies resulted in the discovery of Penta-5-BrAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) and Penta-5-Me(2)NAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which are potent hMC4R agonists and are inactive in hMC1R, hMC3R and hMC5R agonist assays.
Cheung
Adrian Wai-Hing
AW
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. adrian.cheung@roche.com
Danho
Waleed
W
Swistok
Joseph
J
Qi
Lida
L
Kurylko
Grazyna
G
Rowan
Karen
K
Yeon
Mitch
M
Franco
Lucia
L
Chu
Xin-Jie
XJ
Chen
Li
L
Yagaloff
Keith
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000242:Cyclic AMP / Q000096:biosynthesis; D006639:Histidine; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000378:metabolism; D044101:Receptors, Melanocortin; D013329:Structure-Activity Relationship
C474662:Bu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2); D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D006639:Histidine; D000242:Cyclic AMP