2-Phenylcyclopropylmethylamine Derivatives as Dopamine D 2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation

作者：Wenzhong Yan, Luyu Fan, Jing Yu, Ruiquan Liu, Huan Wang, Liang Tan, Sheng Wang, Jianjun Cheng · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c01327 · 被引用次数：15 · 研究领域：Receptor Mechanisms and Signaling、Neurotransmitter Receptor Influence on Behavior、Pharmacological Receptor Mechanisms and Effects

Partial agonist activity at the dopamine D 2 receptor (D 2 R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D 2 R. A number of potent D 2 R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure–functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)- 14j and (+)- 14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT 2A ) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D 2 R partial agonists are effective as potential novel antipsychotics.