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2-（氟甲氧基）-4'-（甲磺酰基）-1,1'-联苯（UCM-1306），一种用于帕金森病的人源多巴胺 D 受体的口服生物可利用的正变构调节剂。

2-(Fluoromethoxy)-4'-(-methanesulfonimidoyl)-1,1'-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D Receptor for Parkinson's Disease.

机构信息

Departamento de Química Orgánica, Universidad Complutense de Madrid, E-28040 Madrid, Spain.

Biofarma Research Group, USEF Screening Platform, CIMUS, USC, E-15782 Santiago de Compostela, Spain.

出版信息

J Med Chem. 2022 Sep 22;65(18):12256-12272. doi: 10.1021/acs.jmedchem.2c00949. Epub 2022 Aug 31.

DOI:10.1021/acs.jmedchem.2c00949
PMID:36044544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9511493/
Abstract

Tolerance development caused by dopamine replacement with l-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson's disease. In search for selective modulators of the D receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound [UCM-1306, 2-(fluoromethoxy)-4'-(-methanesulfonimidoyl)-1,1'-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances l-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound supports the interest of a positive allosteric modulator of the D receptor as a promising therapeutic approach for Parkinson's disease.

摘要

多巴胺替代物 l-DOPA 引起的耐受性发展，以及正构激动剂激活多巴胺能受体带来的治疗弊端，揭示了安全有效治疗帕金森病的巨大未满足需求。为了寻找 D 受体的选择性调节剂，我们对一个已确定的命中化合物进行了化学文库筛选和后续的药物化学研究，得到了一种新的合成化合物[UCM-1306，2-(氟甲氧基)-4'-(-甲磺酰亚胺基)-1,1'-联苯]，它能以剂量依赖的方式增加人和小鼠 D 受体中的多巴胺最大效应，在没有多巴胺的情况下没有活性，调节多巴胺与受体的亲和力，表现出亚型选择性，并且与正构配体的结合竞争较低。这种新型的变构调节剂增强了可卡因诱导的运动，并在给予 reserpine 的小鼠中增强了 l-DOPA 对运动活性降低的恢复作用。该化合物的行为支持 D 受体的正变构调节剂作为治疗帕金森病的一种有前途的治疗方法的兴趣。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b0/9511493/754a3a001907/jm2c00949_0009.jpg

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