The melanocortin signalling system is a fundamental and complex biological pathway with broad physiological functions and considerable therapeutic potential. It consists of five distinct melanocortin receptor subtypes (MC1R–MC5R), which are activated by four endogenous peptide ligands: α-melanocyte-stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). These receptors belong to the G protein-coupled receptor (GPCR) family, and they are widely expressed across diverse tissues, including exocrine glands, epidermis, and the central nervous system. MCRs primarily signal through the cyclic adenosine monophosphate (cAMP) pathway. Although each receptor subtype is broadly distributed throughout the body, they exhibit distinct tissue-specific expression patterns. These differences contribute to a wide range of physiological and pathological processes, including skin pigmentation, energy homeostasis, and inflammation. As a result, melanocortin receptors (MCRs) have emerged as promising targets for therapeutic intervention1,2.
The majority of work has examined side-chain to side-chain bridged peptides such as Asp-Lys lactams (MT-II, bremelanotide) and Cys-Cys disulfides (Setmelanotide). Other architectures have been less studied. Here we have assessed novel head-to-tail and head-to-side-chain linked peptides synthesised at the University of Naples. These peptides feature modifications to the ring size and amino group on the lactam bridge. To investigate MCR function, cAMP accumulation assays were used in MCR-transfected HEK cells. To characterise their binding properties, we employed fluorescence-based competitive binding assays (FACS). This allowed us to investigate the relationship between receptor binding affinity and cAMP-mediated functional activity. We found that the structural modifications significantly influenced receptor subtype-specific activity and selectivity with highlight example FM636 showing sub-nanomolar binding affinity and potent, selective antagonism of MC4R3.