title: End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists.
abstract: Of the 42 R'-X-(p-Cl)Phe-D-Phe-Arg-Trp-NH(2) (X=CO, SO(2), PO, PS) tested at the human (h)MC1, hMC3, and hMC4 receptors (R), the most potent MC4R agonists (EC(50) of 8-20 nM) were obtained by end-capping with R'=CH(2)CHCH(2) (9), NCCH(2) (16), NH(2)COCH(2) (17), HCONHCH(2) (18), CH(3)NH (19), CH(2)CHCH(2)NH (21), 2-Th (23), PhCH(2) (30) and X=CO. These compounds possess 35-60-fold hMC4 versus hMC1Rs selectivity with urea LK-71 (19) being the most potent at hMC4R and MC4/1R selective (EC(50)=8.5 nM, MC4/1R=100). LK-75 (16) combines high potency at hMC4R and MC4/3R selectivity (EC(50)=10.5 nM, MC4/3R=290). SAR is discussed.
authors.affiliation: College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Koikov
authors.forename: F H
authors.initials: FH
authors.lastname: Ebetino
authors.forename: J C
authors.initials: JC
authors.lastname: Hayes
authors.forename: D
authors.initials: D
authors.lastname: Cross-Doersen
authors.forename: J J
authors.initials: JJ
authors.lastname: Knittel
mesh_terms: D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C470072:MC4R protein, human; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH