Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists

Abstract

Differentiation of the physiological role of the melanocortin receptor 5 MC5R from that of other melanocortin receptors will require development of high affinity and selective antagonists. To date, a few synthetic antagonist ligands active at hMC5 receptor are available, but most do not have appreciable selectivity. With the aim to gain more potent and selective antagonists for the MC5R ligands, we have designed, synthesized, and pharmacologically characterized a series of alkylthioaryl-bridged macrocyclic peptide analogues derived from MT-II and SHU9119. These 20-membered macrocycles were synthesized by a tandem combination using solid phase peptide synthesis and microwave-assisted reactions. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues, compounds, 9, 4, and 7, are selective antagonists at the hMC5 receptor. In particular, compound 9 (PG-20N) is a selective and competitive hMC5R antagonist, with IC 50 of 130 ± 11 nM, and a pA 2 value of 8.3, and represents an important tool for further biological investigations of the hMC5R. Compounds 4 and 7 (PG14N, PG17N) show potent and selective allosteric inhibition at hMC5R with IC 50 values of 38 ± 3 nM and 58 ± 6 nM, respectively. Compound 9 will be used to further investigate and more clearly understand the physiological roles played by the MC5 receptor in humans and other animals.

A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids

“…Interestingly, all natural MCRs ligands have somewhat higher affinities for MC1R than MC5R [50], while the opposite is true for JNJ-10229570. A synthetic molecule, compound 9, was found to be a more selective antagonist of the MC5R [51]. It would be of interest to study the effect of compound 9 on sebaceous cell differentiation and lipid production.…”

Region-specific differences in brain melanocortin receptors in rats of the lean phenotype

“…Because MTII is not specific for MC3R, however, we cannot rule out the possibility that other MC receptors in the PVN contribute to physical activity and EE. Though a first step, these results can be further defined by specific localization of function using MCR subtype-specific agonists and antagonists [19,20].…”

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

“…For example, a series of 20-membered macrocyclic peptidomimetics has been recently synthesized using MW-irradiation for the cyclization step [81]. This MW-assisted cyclization occurs through a nucleophilic aromatic substitution (SNAr) between a cysteine and a p-fluoronitrobenzene derivative before the cleavage of the peptide from the resin.…”