The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.
The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.
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DOI：
10.3390/ijms241210145
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发表时间：
2023-06-14
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
黑皮质素受体参与许多生理途径，包括食欲、皮肤和毛发色素沉着以及类固醇生成。特别是，黑皮质素-3受体（MC 3R）参与脂肪储存，食物摄入和能量稳态。为MC 3R开发的小分子配体可以作为治疗能量不平衡疾病状态的治疗性先导化合物。在此，三个先前报道的吡咯烷双环胍化合物与5个位点的分子多样性（R1-R5）进行平行的结构-活性关系的研究，以确定在MC 3R的完全激动所需的这种支架系列的共同药效团。R2、R3和R5位置是完全MC 3R功效所需的，而所有三种化合物中R1或R4位置的截短导致完全MC 3R激动剂。还鉴定了分子量低于300 Da的另外两个片段，其在mMC 5 R处具有完全激动剂效力和微摩尔效力。这些SAR实验可能是有用的，在产生新的小分子配体和化学探针的黑皮质素受体，以帮助阐明其在体内的作用，并作为治疗的铅化合物。
The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1–R5) were subjected to parallel structure–activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.
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影响因子：
7.3
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
通讯作者：
Haskell-Luevano C
影响因子：
2.9
作者：
CHEN, WB;SHIELDS, TS;CONE, RD
通讯作者：
CONE, RD
DOI：
10.1006/bbrc.1993.2125
发表时间：
1993-09-15
影响因子：
3.1
作者：
CHHAJLANI, V;MUCENIECE, R;WIKBERG, JES
通讯作者：
WIKBERG, JES
影响因子：
64.8
作者：
Fan, W;Boston, BA;Cone, RD
通讯作者：
Cone, RD
影响因子：
7.3
作者：
Ericson MD;Doering SR;Larson CM;Freeman KT;LaVoi TM;Donow HM;Santos RG;Cho RH;Koerperich ZM;Giulianotti MA;Pinilla C;Houghten RA;Haskell-Luevano C
通讯作者：
Haskell-Luevano C