Structure−Activity Relationships of γ-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues

Abstract

It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in alpha-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native gamma-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH(2) with Gly(4)) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2')) scan of the gamma-MSH sequence at position 6 and 8 and the replacement of His(5) with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2')-Arg-Trp-Asp-Arg-Phe-Gly-NH(2), which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.

A Novel and Selective β-Melanocyte-Stimulating Hormone-Derived Peptide Agonist for Melanocortin 4 Receptor Potently Decreased Food Intake and Body Weight Gain in Diet-Induced Obese Rats

“…More recently Kavarana et al (39) discovered that another cyclic ␣MSH peptide analog, (O)C-CH2-CH2-c[His6-D-Phe7-Arg8-Trp9-Lys10]amide, was a selective and potent agonist for human MC4R. Furthermore, BalseSchnivasan et al (40) synthesized novel ␣MSH/␤MSH hybrid analogs that led to potent and selective ligands to human MC3R and MC4R. Finally, Oosterom et al (41,42) reported that a major determinant for selective receptor interaction is the conformational presentation of the core sequence in melanocortin peptides directed to the receptor binding pockets of the MC3R and MC4R.…”

Approaches to the rational design of selective melanocortin receptor antagonists

“…The linear γ-MSH analog 17 , H-Tyr-Val-Nle-Gly-His-Phe-Arg-D-Nal(2′)-Asp-Arg-Phe-Gly-NH 2 (Table 4), was found to be a potent and selective antagonist at the hMC4R [60] while the cyclic Pen 3 -Cys 9 analog 18 also is a potent and selective MC4 antagonist [60], a potent partial agonist at the MC1R and a potent full agonist at the MC5R. The D-Nal(2′)-containing analog 18 , on the other hand, is a potent and selective antagonist at the hMC4R, and a moderate potent agonist at the hMC3R (IC 50 = 150 nM) and a weak antagonist (IC 50 = 1700 nM) at the MC5R [60].…”

“…The D-Nal(2′)-containing analog 18 , on the other hand, is a potent and selective antagonist at the hMC4R, and a moderate potent agonist at the hMC3R (IC 50 = 150 nM) and a weak antagonist (IC 50 = 1700 nM) at the MC5R [60]. Compound 19 (Table 4) is an interesting cyclic analog related to γ-MSH [45] which, though a modest binder, has highly selective antagonist activity at the MC4R with no binding to the MC1R, MC3R and MC5R.…”

Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

“…Furthermore, replacement of the oxidizable Met 3 residue with Nle increased the stability of the peptide [52], which is being widely used as a ligand for the hMC3R in a variety of ongoing pharmacological studies and in animal model studies related to the hMC3R. Interestingly, when the Phe 6 residue of γ-MSH was substituted with D-Nal(2′), a substitution known to convert α-MSH analogues to antagonists at the hMC3R and hMC4R [53], the resulting analogue (HTyr-Val-Nle-Gty-His-D-Nal(2′)-Arg-Trp-Asp-Arg-Phe-Gly-NH 2 ) exhibited potent hMC3R/ hMC5R antagonist activity, while retaining potent full agonist activity at the hMC4R [54].…”