Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist

Abstract

To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His(6)-Phe(7)-Arg(8)-Trp(9)-domain. Replacement of His(6) by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).

Novel approaches to the design of bioavailable melanotropins

“…Further in vivo study showed 24% reduction in food intake with rats intracerebroventricularly administrated with this constrained tetrapeptide. Another research used the constrained amino acids Aia, Aba, and Ata to replace His, which led to discovery of three MC4R selective agonists and one MC5R selective antagonist [51]. Two of the MC4R selective agonists were able to reach EC 50 of 0.3 nM, which is even more potent than MT-II.…”

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

“…Fig. ( 6 ) shows the molecular docking result of our novel designed local constrained tetrapeptides: Ac-Aia- p F- D -Phe-Arg-Trp-NH 2 , a selective hMC4R agonist, and Ac-Aba- D -Phe-Arg-Trp-NH 2 , an agonist of the hMC4R; antagonist of the hMC5R, interacted with the hMC4R receptor [65]. In these cases, homology modeling with the few known structures in these classes has been somewhat successful, but further developments are clearly needed.…”

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

“…The study identified four tetrapep- . 117 The presence of an Aia-D-Phe dipeptidomimetic in 145 resulted in weak micromolar antagonist activity for the hMC1R, allosteric partial agonism at hMC3R (EC 50 = 52 nM) and hMC4R (EC 50 = 0.3 nM), and moderate antagonist activity at the hMC5R. Fluorination of the para-position in D-Phe 7 in 146 led to enhanced activity, which was most pronounced at hMC4R (IC 50 = 6.5 nM; EC 50 = 13 nM, full agonist).…”

“…Hence, the insertion of constrained aminobenzo-and indoloazepinone-based residues into the core of melanocortin tetrapeptides resulted in compact and selective human melanocortin receptor ligands with diverse pharmacological profiles. 117…”