Review
This narrative review examines the current and investigational pharmacological treatments for erythropoietic protoporphyrias (EPP), a group of ultra-rare inherited disorders of heme biosynthesis causing severe, painful phototoxic reactions triggered by visible light exposure. The authors searched PubMed and clinical trial databases to synthesize available evidence on two investigational agents—dersimelagon (a melanocortin-1 receptor agonist) and bitopertin (a glycine transport inhibitor)—alongside the only currently approved therapy, afamelanotide. The review notes that afamelanotide effectively reduces pain and extends tolerable sun exposure time but does not address the underlying disease mechanism and is approved only for adults, leaving pediatric patients without a treatment option. The authors report that available trial data for both dersimelagon and bitopertin suggest treatment effects versus placebo, though they emphasize that the safety and efficacy profiles of both agents require further characterization. A key limitation highlighted is the absence of head-to-head comparison data against afamelanotide, which the authors argue is necessary to inform regulatory decisions and ensure meaningful patient access. The review concludes that both agents hold promise but that additional robust clinical evidence is needed before their roles in EPP management can be fully established.
Expert opinion on pharmacotherapy · Mar 2026DOI ↗ Review
This systematic review, conducted following PRISMA guidelines, synthesizes findings from 68 peer-reviewed studies examining the mechanisms, clinical applications, formulations, and adverse effects of four major sunless tanning agents: dihydroxyacetone (DHA), melanotan (I and II), forskolin, and carotenoids. The authors found that DHA produces skin pigmentation through the Maillard reaction (a non-enzymatic browning of amino acids in the stratum corneum) and has shown additional dermatologic utility in vitiligo and erythropoietic protoporphyria, as well as potential antifungal properties—though concerns about cytotoxicity, genotoxicity, and systemic absorption were noted. Melanotan I and II, which act on melanocortin receptors, were associated with serious adverse effects in unregulated use, including rhabdomyolysis, renal infarction, and priapism. Forskolin was reported to stimulate melanin production independently of melanocortin receptors, with efficacy demonstrated primarily in animal models. Orally ingested carotenoids were found to accumulate in skin and subcutaneous fat, producing a yellow-orange hue. The review acknowledges significant limitations: lack of standardized reporting, heterogeneous outcomes across studies, and insufficient long-term human safety data, particularly for forskolin and carotenoids. The authors conclude that further rigorous clinical research and updated regulatory guidance are needed.
The Journal of clinical and aesthetic dermatology · Feb 2026Source ↗ Review
This review paper examines the history, development, and scientific utility of key synthetic tool compounds used to study the melanocortin receptor (MCR) family — a group of five Class A G protein-coupled receptors (GPCRs) involved in diverse physiological processes including pigmentation, steroidogenesis, and energy homeostasis. The authors trace how synthetic derivatives of the endogenous agonist α-MSH, including NDP-MSH (melanotan I), melanotan II (MTII), and SHU9119, have become essential pharmacological tools for the field. The review discusses how these compounds are used to validate cell lines stably expressing melanocortin receptors, serve as reference ligands in high-throughput screening, inform structure-activity relationship (SAR) studies, and act as core ligands in cryo-EM structural investigations of active and inactive receptor complexes. The paper also notes that these tool compounds have served as scaffolds for FDA-approved drugs. Limitations of the review include its descriptive, non-experimental nature and its focus on synthesizing existing literature rather than presenting new empirical data. It provides important context for researchers working on MCR pharmacology but does not itself generate clinical or mechanistic evidence.
ACS pharmacology & translational science · Aug 2024DOI ↗