Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Florida International University, Port St. Lucie, Florida 34987, United States.
J Med Chem. 2021 May 13;64(9):5577-5592. doi: 10.1021/acs.jmedchem.0c02041. Epub 2021 Apr 22.
The central melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy homeostasis. Herein, the discovery and characterization of first-in-class small molecule melanocortin agonists with selectivity for the melanocortin-3 receptor over the melanocortin-4 receptor are reported. Identified via "unbiased" mixture-based high-throughput screening approaches, pharmacological evaluation of these pyrrolidine bis-cyclic guanidines resulted in nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological profiles at the remaining melanocortin receptor subtypes tested indicated similar agonist potencies at both the melanocortin-1 and melanocortin-5 receptors and antagonist or micromolar agonist activities at the melanocortin-4 receptor. This group of small molecules represents a new area of chemical space for the melanocortin receptors with mixed receptor pharmacology profiles that may serve as novel lead compounds to modulate states of dysregulated energy balance.
中央黑皮质素-3 和黑皮质素-4 受体（MC3R、MC4R）是体重和能量平衡的关键调节剂。本文报道了首次发现的一类对黑皮质素-3 受体具有选择性的新型小分子黑皮质素激动剂，其对黑皮质素-4 受体具有选择性。通过“无偏见”的基于混合物的高通量筛选方法鉴定出这些吡咯烷双环胍，它们对黑皮质素-3 受体具有纳摩尔级的激动剂活性。在其余测试的黑皮质素受体亚型中的药理学特征表明，在黑皮质素-1 和黑皮质素-5 受体中具有相似的激动剂效力，而在黑皮质素-4 受体中具有拮抗剂或微摩尔级的激动剂活性。这组小分子代表了黑皮质素受体的一个新的化学空间区域，具有混合的受体药理学特征，可能作为调节失调的能量平衡状态的新型先导化合物。
