Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists.

The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in L-DOPA induced dyskinesias in Parkinson’s disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

多巴胺受体4（D4R）在皮质 - 基底神经节网络的运动、联合和边缘亚区均高度表达。由于其在大脑中的分布，越来越多的证据表明D4R在调节该网络以及随后参与帕金森病中左旋多巴诱导的运动障碍方面发挥着作用。作为我们在发现新型D4R拮抗剂持续努力的一部分，我们报道了一种新的3 - 或4 - 苄氧基哌啶骨架作为D4R拮抗剂的发现和特性。我们报道了几种对D4R具有选择性的化合物（相较于其他多巴胺受体亚型选择性>30倍），其在体外和体内的稳定性较之前报道的D4R拮抗剂有所提高。