Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.
Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.
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DOI：
10.1021/acs.jmedchem.0c02041
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发表时间：
2021-05-13
影响因子：
7.3
通讯作者：
Haskell-Luevano C
中科院分区：
文献类型：
--
作者：
Doering SR;Freeman K;Debevec G;Geer P;Santos RG;Lavoi TM;Giulianotti MA;Pinilla C;Appel JR;Houghten RA;Ericson MD;Haskell-Luevano C
中枢黑素皮质素-3和黑素皮质素-4受体(MC3R、MC4R)是体重和能量平衡的关键调节因子。在这里，发现和表征了一流的小分子黑素皮质素激动剂，其对黑素皮质素-3受体的选择性高于黑素皮质素-4受体。通过基于“无偏”混合物的高通量筛选方法进行鉴定，这些吡咯烷双环鸟苷类药物的药理学评价导致了黑素皮质素-3受体的纳摩尔激动剂活性。其余被测试的黑素皮质素受体亚型的药理学特征表明，黑素皮质素-1和黑素皮质素-5受体的激动剂活性相似，黑素皮质素-4受体的拮抗剂或微摩尔激动剂活性相似。这组小分子代表了黑素皮质素受体的一个新的化学空间，具有混合受体药理学特征，可能作为新的先导化合物来调节能量平衡失调的状态。
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.
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影响因子：
7.3
作者：
Fleeman, Renee;LaVoi, Travis M.;Shaw, Lindsey N.
通讯作者：
Shaw, Lindsey N.
影响因子：
2.9
作者：
CHEN, WB;SHIELDS, TS;CONE, RD
通讯作者：
CONE, RD
影响因子：
2.7
作者：
Cheung, AWH;Danho, W;Yagaloff, K
通讯作者：
Yagaloff, K
影响因子：
8.1
作者：
Collet TH;Dubern B;Mokrosinski J;Connors H;Keogh JM;Mendes de Oliveira E;Henning E;Poitou-Bernert C;Oppert JM;Tounian P;Marchelli F;Alili R;Le Beyec J;Pépin D;Lacorte JM;Gottesdiener A;Bounds R;Sharma S;Folster C;Henderson B;O'Rahilly S;Stoner E;Gottesdiener K;Panaro BL;Cone RD;Clément K;Farooqi IS;Van der Ploeg LHT
通讯作者：
Van der Ploeg LHT
影响因子：
64.8
作者：
Fan, W;Boston, BA;Cone, RD
通讯作者：
Cone, RD