The melanocortin system regulates critical physiological processes, including energy homeostasis and feeding behaviour, via five class A GPCRs (MC1-5R). While FDA-approved cyclic peptide agonists (e.g., setmelanotide and bremelanotide) target these receptors, their clinical utility is limited by poor subtype selectivity (<20-fold) and side effects—stemming from a shared α-MSH-derived peptide pharmacophore. To address this, we explored a constrained cyclic hexapeptide architecture featuring a Glu side-chain to N-terminus lactam bridge (20 backbone heavy atoms). This smaller ring size, distinct from larger clinical peptides (e.g., setmelanotide: 23 atoms), imposes enhanced conformational rigidity to improve selectivity.
We revisited this understudied scaffold first reported by Mayorov et al. (2006),1 by preparing peptides, c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH₂, (1, previously described as an MC3R agonist, IC50 = 140nM, EC₅₀ = 1.2nM) and c[Nle-Val-D-Nal-Arg-Trp-Glu]-NH₂ (2, previously described as an MC5R antagonist, IC50 = 2.2nM). They were prepared by SPPS with on-resin cyclisation, utilising orthogonal Glu protection.
In contrast to the report, peptide 1 was a potent, selective MC4R agonist (EC₅₀ = 0.088nM). Peptide 2, was in fact inactive at MC3R and showed moderate agonist activity at MC1R (EC50 = 35nM) and MC5R (EC50 = 9.6nM). This original mischaracterisation of activities has been described for other peptides from the same laboratories.2
We are continuing to explore this scaffold, revealing unexpected structure-activity relationships (SAR) and selectivity profiles. Molecular simulations are being used to provide mechanistic insights into selectivity and guide rational ligand optimisation. This work validates a compact cyclic architecture as a versatile platform for developing subtype-selective melanocortin receptor ligands with improved therapeutic potential.
1. Mayorov, A.V. et al J. Med. Chem. 2006, 49, 1946-1952
2. Gimenez, L.E. et al J. Med. Chem. 2022, 65, 5990−6000