催化
中棘神经元
帕金森病
基底神经节
神经科学
氟哌啶醇
化学
药理学
药物发现
医学
疾病
兴奋剂
多巴胺
反激动剂
受体
内科学
心理学
纹状体
中枢神经系统
生物化学
作者
Huikai Sun,Holger Monenschein,Hans H. Schiffer,H Reichard,Shota Kikuchi,Maria Hopkins,Todd K Macklin,Stephen Hitchcock,Mark E. Adams,Jason Green,Jason W. Brown,Sean T. Murphy,Nidhi Kaushal,Deanna Collia,Samuel K. Moore,William J. Ray,Nicole M. English,Mark Carlton,Nicola Brice
标识
DOI:10.1021/acs.jmedchem.0c02081
摘要
Parkinson's disease (PD) is a chronic and progressive movement disorder with the urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients. Potent and selective GPR6 inverse agonists (IAG) were developed starting from a low-potency screening hit (EC50 = 43 μM). Herein, we describe the multiple parameter optimization that led to the discovery of multiple nanomolar potent and selective GPR6 IAG, including our clinical compound CVN424. GPR6 IAG reversed haloperidol-induced catalepsy in rats and restored mobility in the bilateral 6-OHDA-lesioned rat PD model demonstrating that inhibition of GPR6 activity in vivo normalizes activity in basal ganglia circuitry and motor behavior. CVN424 is currently in clinical development to treat motor symptoms in Parkinson's disease.
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