2‑Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation

• Published in: Journal of medicinal chemistry Vol. 64; no. 23; pp. 17239 - 17258
• Main Authors: Yan, Wenzhong, Fan, Luyu, Yu, Jing, Liu, Ruiquan, Wang, Huan, Tan, Liang, Wang, Sheng, Cheng, Jianjun
• Format: Journal Article
• Language: English
• Published: American Chemical Society 09.12.2021
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01327

Partial agonist activity at the dopamine D2 receptor (D2R) 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 D2R. A number of potent D2R 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-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.