Design, synthesis, and biological evaluation of a new class of small molecule peptide mimetics targeting the melanocortin receptors

Abstract

A new bicyclic template has been developed for the synthesis of peptide mimetics. Straightforward synthetic steps, starting from amino acids, allow the facile construction of a wide range of analogs. This system was designed to target the melanocortin receptors (MCRs), with functional group selection based on a known pharmacophore and guidance from molecular modeling to rationally identify positional and stereochemical isomers likely to be active. The functions of hMCRs are critical to myriad biological activities, including pigmentation, steroidogenesis, energy homeostasis, erectile activity, and inflammation. These G-protein-coupled receptors (GPCRs) are targets for drug discovery in a number of areas, including cancer, pain, and obesity therapeutics. All compounds from this series tested to date are antagonists which bind with high affinity. Importantly, many are highly selective for a particular MCR subtype, including some of the first completely hMC5R-selective antagonists reported. Keywords Melanocortins; Peptide mimetics; GPCRsThe human melanocortin receptors (hMCRs) comprise a family of five Type I, or rhodopsinlike, G-protein-coupled receptors (GPCRs) to which a wide array of biological functions has been ascribed. 1 Some examples include nociception, inflammation, energy balance, and sexual function. From the early understanding of the role MCRs play in pigmentation to recent revelations concerning their relevance to pain, new studies have continually uncovered crucial but previously unknown actions of this receptor system. Beyond advancing our knowledge of basic biology, the understanding and modulation of MCR function also has clinical relevance, with potential therapeutic value for addressing obesity, 2 cachexia, 3 pain, 4 inflammatory diseases, 5 and sexual dysfunction, 6 as well as the diagnosis and treatment of certain cancers. 7Much research to date has relied on natural and synthetic peptide ligands for these receptors. The MCRs are unique in that both endogenous agonists (α-, β-, γ-MSH, ACTH) and antagonists (agouti, AGRP) for the system have been discovered. 8 Each of the agonists contains the HisPhe-Arg-Trp tetrad, the minimum sequence necessary for activation of all melanocortin receptors. 9 Both endogenous antagonists contain an Arg-Phe-Phe sequence. Extensive melanotropin peptide structure-activity relationship (SAR) studies by our group and others have identified modifications which enhance potency, stability, or selectivity. 10 The value of

Approaches to the rational design of selective melanocortin receptor antagonists

“…Grieco et al [80] developed an alkylthioaryl-bridged macrocyclic peptide template related to the MT-II and SHU-9119 and the analogs obtained produced several cyclic ligands of varying potencies and MC5R antagonist selectivities ( 37 – 39 , Table 5) [81]. These 20-membered macrocycles were synthesized by a tandem combination using solid phase peptide synthesis and microwave-assisted reactions.…”

“… NB: No binding at 10 −5 M; NA: No activity at 10 −5 M. ‡ Potential allosteric ligand for hMC5R based on the partial binding efficacy [81]. …”

Melanotropins as Drugs for the Treatment of Obesity and Other Feeding Disorders: Potential and Problems

“…2 and 3 [74]. These very minimal structures related to the melanocortin peptide pharmacophore have very interesting biological properties.…”

β-Turn secondary structure and melanocortin ligands

“…Based on the observation that the majority of small molecules with activity at the melanocortin receptors contain two aromatic hydrophobic groups and a group with a basic nitrogen, the group synthesized a series of small molecules to investigate the effects of substitution of the hydrophobic residues, the orientation of the hydrophobic groups, and the significance of the basic Arg residue based on a template synthesized from LPro and D,L-Phe. 63 Many of the resulting small molecules were capable of binding to one or more of the hMCRs at nanomolar concentrations, some exhibiting selectivity for the hMC5R. Though many of the compounds were unable to stimulate a cAMP response, a new small molecule template capable of binding to the melanocortin receptors was identified.…”