Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.
Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.
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小鼠黑皮质素受体上取代尿素衍生物的合成和构效关系。
DOI：
10.1021/acschemneuro.5b00273
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发表时间：
2016
影响因子：
5
通讯作者：
Haskell-Luevano,Carrie
中科院分区：
文献类型：
--
作者：
Singh,Anamika;Kast,Johannes;Dirain,MarvinLS;Huang,Huisuo;Haskell-Luevano,Carrie
黑皮质素系统参与调节几种复杂的生理功能。特别地，黑皮质素-3和-4受体（MC 3R/MC 4 R）已被证明调节体重、能量稳态和进食行为。合成和内源性黑皮质素激动剂已在啮齿动物模型中显示出致毒性。本文报道了27个以不对称取代脲为核的非肽类小分子配体的合成和构效关系研究。设计并合成了三个模板，这些模板包含来自先导化合物的关键残基，在三个位置（R1，R2，R3）显示多样性。的合成进行了优化，有效的微波辅助化学显着减少总合成时间相比，以前报道的室温方法。化合物对小鼠黑皮质素受体的药理学表征鉴定出化合物1和12对mMC 4 R具有完全激动剂活性，但当测试浓度高达100 μM时，未观察到对mMC 3R的活性。SAR鉴定的化合物在R1位具有脂族或饱和环胺，在R2位具有大体积芳族基团，在R3位具有苄基，导致mMC 4 R的选择性超过mMC 3R。本系列的小分子模板和构效关系知识可能有助于进一步设计MC 3R/MC 4 R选择性小分子配体。
The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure–activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R1, R2, R3), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds1and12with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 μM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R1position, bulky aromatic groups at the R2position, and benzyl group at the R3position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands.