End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 19; pp. 4839 - 4842
• Main Authors: KOIKOV, L. N, EBETINO, F. H, HAYES, J. C, CROSS-DOERSEN, D, KNITTEL, J. J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 04.10.2004
• Subjects: alpha-MSH - chemical synthesis; alpha-MSH - pharmacology; Biological and medical sciences; Humans; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptor, Melanocortin, Type 4 - agonists; Structure-Activity Relationship; Human; Agonist; Peptides; MC4 melanocortin receptor; Tetrapeptide; Ureas; Selectivity; Chemical synthesis; Biological activity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.046

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.