Sub-nanomolar hMC1R agonists by end-capping of the melanocortin tetrapeptide His-D-Phe-Arg-Trp-NH(2).
Twenty three derivatives of the core fragment His(6)-D-Phe(7)-Arg(8)-Trp(9)-NH(2) end-capped with carboxylic and sulfonic acids were synthesized and evaluated at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). The SAR within this series allowed us to map the hMCRs near the His(6) binding site and design a superpotent MC1R agonist, LK-184, Ph(CH(2))(3)CO-His-D-Phe-Arg-Trp-NH(2) (19) with EC(50) 0.01 nM (5 nM at MC3 and MC4Rs).
Koikov
L N
LN
College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA. lkoikov@hotmail.com
Ebetino
F H
FH
Solinsky
M G
MG
Cross-Doersen
D
D
Knittel
J J
JJ
D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008956:Models, Chemical; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry; D000521:alpha-MSH / Q000737:chemistry
D002264:Carboxylic Acids; D009842:Oligopeptides; D010446:Peptide Fragments; C484474:Ph(CH(2))(3)CO-His-D-Phe-Arg-Trp-NH(2); D044102:Receptor, Melanocortin, Type 1; D013451:Sulfonic Acids; D006639:Histidine; D000521:alpha-MSH