Discovery and Characterization of Novel CNS |
您所在的位置：网站首页 › richardcmartin › Discovery and Characterization of Novel CNS |
Discovery and Characterization of Novel CNS
|
From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson’s disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited β-arrestin signaling and receptor desensitization, indicating biased signaling. A compound that showed minimal GPR55 desensitization demonstrated a reduction in firing frequency of medium spiny neurons cultured from rat striatum but did not reverse motor deficits in a rat hypolocomotion model. Further profiling of several desensitizing and non-desensitizing lead compounds showed that they are selective over related cannabinoid receptors CB1 and CB2 and that unbound brain concentrations well above the respective GPR55 EC50 can be readily achieved following oral administration. The novel brain-penetrant GPR55 agonists disclosed can be used to probe the role of this receptor in the brain.
中文翻译：
根据 NETSseq 衍生的人脑转录组数据，我们确定 GPR55 是治疗帕金森病患者运动症状的潜在分子靶点。通过高通量筛选，我们鉴定并优化了对人类和大鼠 GPR55 具有纳摩尔效力的激动剂。我们发现化合物具有强或有限的 β-arrestin 信号传导和受体脱敏，表明信号传导存在偏差。一种表现出最小 GPR55 脱敏作用的化合物表明，从大鼠纹状体培养的中型多棘神经元的放电频率降低，但在大鼠运动不足模型中并没有逆转运动缺陷。对几种脱敏和非脱敏先导化合物的进一步分析表明，它们比相关大麻素受体 CB 1和 CB具有选择性如图2所示，口服给药后可以很容易地达到远高于各自GPR55 EC 50的未结合脑浓度。所公开的新型脑渗透性GPR55激动剂可用于探测该受体在大脑中的作用。 |
【本文地址】