Highly Selective Cyclic Peptides for Human Melanocortin-4 Receptor (MC-4 R): Design, Synthesis, Bioactive Conformation, and Pharmacological Evaluation as an Anti-Obesity Agent

Structure–Activity Relationships of Peptides Incorporating a Bioactive Reverse-Turn Heterocycle at the Melanocortin Receptors: Identification of a 5800-fold Mouse Melanocortin-3 Receptor (mMC3R) Selective Antagonist/Partial Agonist versus the Mouse Melanocortin-4 Receptor (mMC4R)

“…All of these compounds, 3, 7, 12, and 16 resulted in full agonists with μM EC 50 values (Table 1). Substitution of His with Pro ( 5 ) and Phe ( 4 ) did increase MC4R versus MC3R agonist ligand selectivity, consistent with previous reports, 44, 50 but were different than previous results using the chimeric peptide template KAR , which resulted in mMC3R antagonists (Figure 7). 37 Compound 6 , with Pro substitution of the DPhe, resulted in a full MC3R agonist with 32-fold decreased activity, with a similar agonist potency of 13200 nM as observed in the KAR template.…”

“…The His residue has been previously studied in pentapeptides, 44–49 tetrapeptides 50 and other peptide templates. 21, 51 Herein, the His side chain was substituted with Ala, discussed above, as well as with the Phe ( 4 ) and Pro ( 5 ) side chains.…”

“…It has been reported previously in the literature that modification at the His side chain position could result in MC4R versus MC3R selectivity. 44, 50, 78, 79 In the peptide-heterocyclic template examined herein, replacement of imidazole side chain of His with the amino acids Ala, Phe, and Pro resulted in a modest reduction in MC3R agonist activity, equipotent MC4R, and minor (up to 15-fold) MC4R versus MC3R selectivity. Unexpectedly, 26 substitution of DPhe with DNal(2′) in the template examined herein resulted in an equipotent MC4R agonist.…”

Extensive structure–activity studies of lactam derivatives of MT‐II and SHU‐9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5

“…This compound was found to be more potent as an antagonist at the h MC3R and the h MC4R, and was a full agonist at the h MC5R. We demonstrated, for the first time and in contrast with other published results (22), that the His 6 position is not very important for melanocortin receptor interaction, and recently other authors also have reported the synthesis of selective agonists at h MC4R by replacing His 6 with unnatural amino acids (23). The present study is aimed at the synthesis of MT‐II and SHU‐9119 analogs with high affinity and selectivity at h MC4R vs. the h MC3R and h MC5R, and the h MC5R vs. the h MC3R and h MC4R.…”

Structure−Activity Relationships of the Melanocortin Tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the Mouse Melanocortin Receptors. 1. Modifications at the His Position

“…Modification of the His 6 by Pro in the MTII peptide template (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 ) , resulted in the identification of modifications that might lead to increased MC4R selectivity versus the MC3R. − More recently, modification of the MTII lactam cyclization ring size of peptides containing the His-DPhe-Arg-Trp sequence resulted in the identification of 50-fold and 90-fold MC4 versus MC3 receptor selectivity. Incorporation of the unusual amino acid Atc in its racemic form (Figure ) at the 6 position in the peptide c[Asp-(racemic)Atc-DPhe-Arg-Trp-Lys]-NH 2 resulted in a peptide possessing 65 nM agonist activity at the human MC4R while possessing only slight agonist activity at the hMC3R, resulting in the most MC4R versus MC3R selective compound disclosed to date .…”