Structure−Activity Relationships of Novel Cyclic α-MSH/β-MSH Hybrid Analogues That Lead to Potent and Selective Ligands for the Human MC3R and Human MC5R

Abstract

It has been shown by extensive studies that alpha-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R. The structure-activity relationships study here is aimed at identifying lead structures or templates of this core sequence by the use of different conformational constraints that might impart changes in its topography and thus promote differences in potency and selectivity at these receptors. Our peptide library consists of a novel series of cyclic alpha-MSH analogues that have disulfide bridges between Cys or Cys-like residues at positions 4 and 10, giving rise to 23-membered rings fused at the C-terminal end with the C-terminal fragment of beta-MSH (Pro-Pro-Lys-Asp). While such constraints of the peptide backbone with disulfide bridges of different chirality affect potency and selectivity at these receptors, further changes in the hydrophobicity at position 7 with either a D-Phe or D-Nal(2') and replacement of a His with a Pro in position 6 cause additional effects. Thus, the most interesting lead compounds that emerged from this study are (1) compound 5, Ac-c[Cys-Glu-His-D-Phe-Arg-Trp-D-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 10 nM), which is the first potent and highly selective antagonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cys-Glu-Pro-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 31 nM), which is a highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the hMC5R; and (3) compound 9, Ac-c[Pen-Glu-His-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 3 nM), which is more potent than 7 at the MC3R but not as selective.

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

“…PG946 is a moderately selective Mc3r antagonist [3]. Peripheral injections of an Mc3r agonist were recently reported to increase food intake, perhaps through regulation of neurons expressing the potent orexigens Neuropeptide Y and AgRP in the arcuate nucleus [26].…”

“…The initial objective was to examine the physiologic response to long term peripheral treatment with a sub-threshold dose of PG932. A second objective was to examine the effect of PG946, a cyclic α-MSH/β-MSH hybrid that is a selective Mc3r antagonist [3], on food intake. Food intake and body weight during the lead-in period, the 7 days prior to treatment, were not significantly different between groups (Fig.…”

“…PG932 has the same affinity as SHU9119 at the Mc3r, with evidence for a modest (7-fold) selectivity for the Mc4r [15]. The second peptide, PG946, is a cyclic α-MSH/β-MSH hybrid that is a selective Mc3r antagonist [3]. Since the peripheral administration of D-trp8-γMSH can increase food intake [26], we were interested in determining whether PG-932 administered peripherally would have an anorectic effect.…”

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

“…The biological results of this series of compounds clearly indicate that a conformational restriction with bulky amino acids in position 6 in a cyclic peptide can be used to obtain selective antagonists for the hMC3R and the hMC4R (pA 2 = 9.1-9.8) [61]. (Table 1) [63].…”

Approaches to the rational design of selective melanocortin receptor antagonists

“…The first highly selective hMC5R ligand was a cyclic disulfide-containing derivative of an α-MSH–β-MSH hybrid where the cyclic part was α-MSH related and the C-terminal β-MSH related ( 36 , Table 5) [79]. As shown in Table 5, 36 is a potent (IC 50 =10 nM) hMC5R antagonist that does not bind to the hMC1R, and hMC4R.…”