Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects

Melanocortins are a group of hormones that play crucial roles in regulating various physiological processes, including stress response, inflammation, and skin pigmentation. These hormones are polypeptides derived from pro-opiomelanocortin (POMC) and include adrenocorticotropin hormone (ACTH), α-, β-, and γ-melanocyte stimulating hormone (α-, β-, and γ-MSH) [ 1 , 2 ]. While the functions of ACTH [ 3 ] and α-MSH are well-established in skin pigmentation [ 4 ], anti-inflammatory [ 5 ], and microbicidal characteristics [ 6 ], the role of β-MSH and γ-MSH are less well understood. Some studies suggested that they possess anti-inflammatory properties [ 7 , 8 , 9 , 10 ]. The functions of melanocortin peptides are mediated by G protein-coupled receptors (GPCRs), primarily the stimulatory G protein (Gs) [ 11 ]. The melanocortin receptor family is the smallest member of class A, a rhodopsin-like family of GPCRs, and consists of five isotypes (MC1R, MC2R, MC3R, MC4R, and MC5R) with varied tissue expression and functions [ 12 ]. MC1R, mainly expressed in both melanocytes and leukocytes, enhances UV resistance and anti-inflammatory signaling when activated. MC2R is found in the adrenal cortex, and both MC3R and MC4R, which are reported to control food intake and sexual function, are largely present in the CNS. MC5R, located in the brain and skeletal muscle, has an exocrine role. The low sequence homology (40–60%) among the five receptors explains the lack of ligand selectivity [ 13 , 14 , 15 , 16 ]. The MC1R is a well-known receptor for α-MSH expressed in the skin and hair follicles, where it controls pigmentation. However, recent studies have revealed that MC1R is also expressed in various other cell types that are susceptible to the anti-inflammatory effects of melanocortins [ 17 , 18 ]. Thus, understanding the regulation of MC1R could potentially lead to the development of novel therapeutic strategies. This review article provides a brief overview of the structure, signaling pathway, and related diseases associated with MC1R and discusses the potential of synthetic peptide modulators and small molecule modulators of MC1R as therapeutic agents. Through a detailed examination of MC1R and its modulators, this review aims to provide insights into the potential clinical implications of modulating MC1R activity.

The melanocortin 1 receptor (MC1R) is a receptor that forms a complex with heterotrimeric G proteins. When agonistic ligands bind to MC1R, the Gαs protein is separated, and MC1R activates adenylyl cyclase, which leads to the production of cAMP, a crucial second messenger that regulates many cellular processes. In melanocytes, cAMP activates protein kinase A (PKA) and triggers downstream signaling pathways that activate different effector pathways, including the CREB and MITF networks. These pathways lead to the increased expression of tyrosinase and dopachrome tautomerase, two enzymes that are involved in melanin synthesis, resulting in the production of melanin. The melanin produced is then transmitted to nearby keratinocytes, creating a protective layer that improves the skin’s ability to prevent further UV damage. Moreover, the increase in cAMP levels in melanocytes enhances antioxidant defenses and accelerates nucleotide excision repair (NER), which is vital for safeguarding the skin from UV damage ( Figure 1 ) [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Moreover, it is also reported that there is a cAMP-independent pathway mediated by cKIT, which is not discussed in this review. This pathway activates the extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2) by triggering the NRAS-BRAF-MEK-ERK cascade and active ERKs can phosphorylate MITF. Furthermore, it has been suggested that the activation of AKT downstream of α-MSH may also occur via cKIT [ 44 ]. Furthermore, the MC1R signaling axis has an anti-inflammatory effect through downstream pathways. When α-MSH binds to MC1R, it triggers the production of intracellular cAMP, which activates protein kinases C and A, leading to the activation of the MAPK and JAK-STAT pathways. These pathways prevent IκB degradation and activate CREB, a transcription factor that regulates anti-inflammatory mediators such as IB and IL-10. In addition, protein kinase activation enhances the levels of cytoplasmic IκB, inhibiting the expression of downstream pro-inflammatory genes, including IL-1, TNF-a, IL-6, IL-8, and IL-12, iNOS, and adhesion molecules (ICAM-1, VCAM-1, and MMPs) ( Figure 2 ) [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ].

Systemic sclerosis (SSc), or scleroderma, is an autoimmune disorder characterized by dysregulation of the immune system and inflammation, microvascular dysfunction, and widespread fibrosis in various organs [ 71 ]. While no approved medications exist for SSc apart from those for SSc-associated ILD (interstitial lung disease), there is a pressing need for innovative treatments that can effectively target fibrosis in multiple organs, including the skin [ 72 , 73 , 74 ]. Activating the melanocortin 1 receptor has been shown to have broad anti-inflammatory and antifibrotic effects. Thus, a recent study investigated the potential of a novel oral MC1R agonist, dersimelagon (MT-7117), as a treatment for SSc. In preclinical SSc models, MT-7117 exhibited disease-modifying effects. Target expression analysis and research into its mode of action indicated that MT-7117 has a favorable effect on inflammation, vascular dysfunction, and fibrosis, all of which are key pathologies in SSc. These findings suggest that MT-7117 may have potential as a treatment for SSc. A phase 2 clinical trial is currently underway to evaluate the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc [ 74 ]. More information about dersimelagon will be discussed in the section on small molecule modulators.

Monocytes and macrophages are known to express the MC1R, which mediates anti-inflammatory effects and helps prevent macrophage foam cell production by increasing cholesterol efflux via ABCA1 and ABCG1 transporters [ 80 , 81 , 82 ]. Recently, a study investigated whether a systemic deficiency of MC1R signaling affects the development of atherosclerosis. The study highlighted the significant role of MC1R in the development of atherosclerosis. The findings suggested that a lack of MC1R signaling may exacerbate atherosclerosis by disrupting cholesterol transport and increasing arterial monocyte deposition [ 83 ]. Furthermore, MC1R plays a role in immunomodulation. Specifically, α-MSH has been shown to decrease pro-inflammatory cytokines in various pulmonary inflammatory disorders, including asthma, sarcoidosis, and acute respiratory distress syndrome. Animal models of pulmonary fibrosis have also demonstrated that α-MSH can reduce fibrogenesis [ 84 ]. In addition to the diseases previously mentioned, MC1R has also been implicated in other diseases, such as intestinal and ocular inflammation [ 85 ] and Parkinson’s disease [ 86 ]. Recent research has shown that modulating MC1R may have therapeutic potential for the diseases previously mentioned.

As previously explained, the endogenous ligands for melanocortin receptors are ACTH and α-, β-, γ-MSH. The most important finding in early drug development was that the amino acid sequence, His6-Phe-Arg-Trp9, was the key sequence needed to activate the melanocortin receptor [ 98 ]. And the sequence was modified to solve the instability, which was a problem of α-MSH, leading to the development of [Nle4, D-Phe7]-α-MSH (melanotan I) [ 99 , 100 ]. Additionally, studies on the cyclization of peptides were conducted to obtain melanotan II using NDP-MSH as a scaffold [ 101 , 102 ]. With these findings, efforts are currently underway to produce selective and stable peptides on the melanocortin 1 receptor, such as PL-8177 [ 67 ]. Among them, we would like to introduce melanotan I and II, which are key substances in the development of peptide drugs ( Figure 4 ). 4.2.1. Melanotan I (MT-I) Melanotan I is an early analog of α-MSH that acts as a non-selective agonist of melanocortin receptors and stimulates melanin production. During the development of peptide-based drugs, researchers focused on the common sequence of MSH, namely His6-Phe-Arg-Trp9, and further studies were conducted on this sequence ( Figure 4 ) [ 98 ]. Eventually, in the frog skin bioassay, it was observed that Ac(Acetyl)-α-MSH7-10-NH2 and Ac-α-MSH6-8-NH2 had no activity, while Ac-α-MSH6-9-NH2 did. This led to the discovery that the minimal sequence required for the biological activity of α-MSH is His6-Phe-Arg-Trp9 [ 99 ]. Furthermore, to increase the stability of the initial α-MSH analog, Sawyer et al. replaced Phe at position 7 with D-Phe and Methionine at position 4 with the amino acid norleucine to prevent oxidation of methionine, as highlighted in green ball. These changes resulted in the production of [Nle4, D-Phe7]-α-MSH (NDP-MSH, melanotan I), a peptide with higher potency and stability than α-MSH [ 100 ]. When melanotan I activates MC1R, cAMP is produced, and it activates microphthalmia transcription factor (MITF) expression, which induces the expression of enzymes for eumelanin production. This process increases the production of eumelanin in melanocytes. In addition, melanotan I activates tyrosinase and induces an increase in eumelanin content in melanocytes [ 103 , 104 , 105 ]. Afamelanotide, well-known as the international nonproprietary name of melanotan I, has been used in patients with erythropoietic protoporphyria (EPP) since 2019. EPP is a disease that causes abnormal hemoglobin synthesis in red blood cells, which can cause skin damage even with a little sunlight. When afamelanotide binds to MC1R, it activates melanocytes and stimulates eumelanin synthesis. Eumelanin protects against UV light by absorbing and scattering it, scavenging free radicals and reactive oxygen species, and acting as a neutral density filter capable of decreasing transmission of all wavelengths of light [ 106 , 107 ]. Recent studies have shed light on the binding structure of MC1R and ligands, while no information has yet been disclosed about the binding structure of receptors and peptides. Afamelanotide, the compound that was switched from Phe7 to D-Phe7 in α-MSH, has an extra hydrogen bond with the TM2 domain in D-Phe7. It has been demonstrated that afamelanotide has a higher affinity for receptors than α-MSH, as evidenced by its capacity to make cAMP, which is superior to α-MSH, as determined by various mutants ( Figure 5 ) [ 35 ].

As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. However, α-MSH not only binds to MC1R but also other melanocortin receptors. This leads to diverse physiological changes including sexual function and immunomodulation. Furthermore, the short half-life of peptide drugs has been suggested as a major obstacle. This emphasizes the need for potent and highly selective MC1R agonists, distinct from α-MSH, to effectively treat vitiligo. In 2023, Zhu et al. introduced a novel MC1R agonist capable of self-assembling into nanofibrils ( Figure 8 ). This peptide, known as Peptide 1, forms a hydrogel that exhibits enhanced stability compared to free peptides. Notably, this hydrogel demonstrates resistance to enzymatic proteolysis. In vitro and ex vivo experiments have convincingly shown that Peptide 1 stimulates MC1R and enhances melanin production by activating tyrosinase and tyrosinase-related protein. Researchers propose that these findings support the MC1R agonist hydrogel as a promising treatment for vitiligo. Moreover, the peptide hydrogel shows potential for preventing UV-induced melanoma and other skin cancers. Consequently, Zhu et al. suggest that this selective and potent MC1R agonist hydrogel presents an alternative for the treatment or prevention of skin pigmentation disorders such as EPP and melanoma [ 70 ].

MT-7117, or dersimelagon, is a selective agonist of MC1R that has been found to have a much higher selectivity for MC1R than NDP-MSH (afamelanotide), a peptide effective in treating erythropoietic protoporphyria (EPP). In binding affinity and agonistic activity measurement experiments conducted by Suzuki et al., MT-7117 was demonstrated to have a Ki value of 2.26 nM for hMC1R (human MC1R), with much higher selectivity ranging from at least 15 to as much as 700 times compared to other receptors ( Figure 10 ). On the other hand, NDP-MSH showed only a 10-fold difference in selectivity for MC1R compared to other receptors, which suggested that NDP-MSH has lower selectivity than MT-7117 [ 123 ]. Due to issues with enzyme stability associated with peptide drugs and higher selectivity for MC1R, MT-7117 has been recently approved in Europe as an alternative treatment for EPP [ 116 ]. A recent study revealed that MT-7117 exhibits anti-inflammatory effects [ 74 ]. The study showed that daily oral administration of MT-7117 to rats with fibrosis induced by bleomycin significantly delayed skin fibrosis and lung inflammation. In addition, it was found to significantly reduce the expression of ACTA2 (α-smooth muscle actin) mRNA in human skin fibroblasts that had been increased by TGF-β. This effect was attributed to the inhibition of inflammatory signaling pathways such as IL-6 signaling. Based on these effects, a clinical trial is currently underway to investigate the association of MT-7117 with SSc patients.

Selective novel MC1R agonists were discovered by the research group in GALDERMA research and development in 2013 [ 120 ]. Imidazolyl-linked azetidine derivatives were synthesized and evaluated for activity for human melanocortin receptors. Among them, CD08108 exhibited a significant hMC1R agonistic activity with EC50 of 70 nM and showed the selectivity of MC1R over MC4R up to 64 times ( Figure 12 ). In 2015, Boiteau et al. reported an efficient synthetic route for CD08108 in a kilogram scale [ 126 ]. CD08108 has been implicated in the process of melanogenesis, indicating its potential as a therapeutic target for the treatment of skin conditions such as hypodermic or photosensitive diseases.

The discovery of the melanocortin 1 receptor several decades ago has led to extensive research into its potential as a therapeutic target. Studies have revealed that the MC1R signaling pathway is crucial in treating melanoma, as it affects various physiological changes in melanocytes. However, recent research has also shown a growing interest in investigating the molecular mechanisms responsible for the non-pigmentary effects of MC1R, particularly in the treatment of inflammatory diseases. Ongoing investigations suggest that drugs targeting MC1R may hold promise in treating patients with high-need conditions such as systemic sclerosis, neuroinflammation, rheumatoid arthritis, fibrosis, and others. With numerous innovative molecules and clinical trials currently underway, it is possible that these drugs may soon improve the quality of life for those with chronic inflammatory conditions. Furthermore, the development of MC1R ligands using multiple chemistry approaches and knowledge of the receptor’s crystal structure may lead to the creation of additional drugs to treat new conditions in the future.