Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH 2) 3CO-His- d-Phe-Arg-Trp-NH 2]. An additional binding site within the human melanocortin receptor 1?

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 15; pp. 3997 - 4000
• Main Authors: Koikov, L.N, Ebetino, F.H, Solinsky, M.G, Cross-Doersen, D, Knittel, J.J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02-08-2004; Elsevier
• Subjects: Binding Sites; Biological and medical sciences; Humans; Kinetics; Medical sciences; Melanocortin agonists; 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 1 - agonists; Receptor, Melanocortin, Type 1 - chemistry; Structure-Activity Relationship; Melanocortin agonists; Human; Agonist; Peptides; Binding site; Biological activity; Melanocortin receptor; MC1 melanocortin receptor; MC4 melanocortin receptor; Tetrapeptide; Analog; Aromatic compound; Chemical synthesis; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.05.039

Of the 29 analogs of LK-184 (
1) tested at the human MC1, MC3, and MC4 receptors (R), only LK-312 (
3), partially mimicking the π-system of
1, had an EC
50 of 0.05
nM at MC1R (0.01
nM for
1). This confirms the localization of a π-binding zone in MC1R. Truncation of (
1) to LK-394 (
30) gave a full MC1 agonist (EC
50 5
nM) with a partial agonism at MC3/4Rs. This suggests the existence of an additional binding site in hMC1R near that for the core sequence His-
d-Phe-Arg-Trp-NH
2.
Twenty nine analogs of a superpotent MC1R agonist LK-184 (
1) were tested at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). All derivatives with the spacer between the N-terminus and the aromatic ring longer or shorter than C
3 were much less potent at hMC1R than
1. Only LK-312 PhCO(CH
2)
3CO-His-
d-Phe-Arg-Trp-NH
2 (
3), partially mimicking the π-system of
1, had an EC
50 of 0.05
nM at hMC1R, which confirms the localization of the π-binding zone of the receptor. Truncation of
1 to Ph(CH
2)
3CO-His-
d-Phe-Arg-NH
2 gave a full MC1 agonist, LK-394 (
30), with an EC
50 of 5
nM and a weak partial agonism at MC3/4Rs. This suggests the existence of an additional binding site within hMC1R next to that for the core sequence His-
d-Phe-Arg-Trp-NH
2.