Joy Stephen T, Dahir Naima S, Cone Roger D, Mapp Anna K
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 49109.
Pept Sci (Hoboken). 2025 Jan;117(1). doi: 10.1002/pep2.24385. Epub 2024 Nov 22.
The melanocortin-3 receptor (MC3R) is a G-protein coupled receptor that regulates appetite and is a potential therapeutic target for anorexia and weight loss treatments. The report of a highly selective synthetic antagonist of MC3R, Cpd11, represents a major advance towards therapeutic targeting of MC3R. However, Cpd11 is challenging to access synthetically, severely limiting its use and additional structural optimization. Here, we outline an improved synthesis of Cpd11 that addresses three major synthetic challenges, including the formation of Cpd11's structurally unique bicyclic core. With these changes, Cpd11 was readily produced (2.3 mg from a .05 mmol scale versus << 0.1 mg using the original synthetic methodology) and utilized in MC3R studies in C57BL/6J male mice. Thus, this new approach will increase the accessibility of Cpd11 and is translatable to related bicyclic agonists and antagonists for other melanocortin receptors and may have general applicability toward the synthesis of other multicyclic poly-cysteine peptides.
黑皮质素-3受体（MC3R）是一种G蛋白偶联受体，可调节食欲，是厌食症和减肥治疗的潜在治疗靶点。一种高度选择性的MC3R合成拮抗剂Cpd11的报道是MC3R治疗靶向的一项重大进展。然而，Cpd11的合成具有挑战性，严重限制了其使用和进一步的结构优化。在此，我们概述了一种改进的Cpd11合成方法，该方法解决了三个主要的合成挑战，包括形成Cpd11结构独特的双环核心。通过这些改进，Cpd11易于制备（从0.05 mmol规模可得2.3 mg，而使用原始合成方法产量远低于0.1 mg），并用于C57BL/6J雄性小鼠的MC3R研究。因此，这种新方法将提高Cpd11的可及性，并可转化为用于其他黑皮质素受体的相关双环激动剂和拮抗剂，可能对其他多环聚半胱氨酸肽的合成具有普遍适用性。
