Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

Abstract

The processed products of the proopiomelanocortin gene (ACTH, α-MSH, β-MSH, γ-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The roeianocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.

Development and in Vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor

“…32–34 MC2R is not avid for MSH-based ligands. 35 MC3R and MC4R are primarily expressed in the human brain and CNS 36–38 However, MC3R mRNA has been detected in human heart and MC5R mRNA is expressed in human lung and kidney. 39 Expression in the brain is less of a concern because MSH-based targeted agents are not likely to cross the blood-brain barrier.…”

C‐terminal tails mimicking bioactive intermediates cause different plasma degradation patterns and kinetics in neuropeptides γ‐MSH, α‐MSH, and neurotensin

“…[19][20][21] A major problem facing the use of MSHs in clinic is limited plasma halflife. Classical pharmaceutical chemistry structure-activity relationships have been focused on the shorter peptide forms, 22 whereas little is known on the influence of the extra regions on the chemical-physical and biological properties of the hormones per se.…”

In Vivo and in Silico Pharmacokinetics and Biodistribution of a Melanocortin Receptor 1 Targeted Agent in Preclinical Models of Melanoma

“…In addition, they can used to follow therapy response. Such probes could also be used for the intraoperative margin assessment and detection of regional lymph node involvement during surgery 20, 21 and there is increasing interest in the use of novel targeted therapies for melanoma, which is notoriously resistant to most systemic therapies. 11 For example, by attachment to a targeted agent with a cleavable linker, cytotoxins may be targeted to tumor cells for receptor-mediated endocytosis and intracellular release 12 , increasing the effective local concentration at the metastasis, while maintaining tolerable systemic levels of cytotoxin, i.e., increasing the therapeutic window.…”

“…The other two MSH avid melanocortin receptor isoforms (MC3R and MC4R) are primarily expressed in the brain and CNS, which is protected by the blood brain barrier. 20–22 …”