2-Phenylcyclopropylmethylamine Derivatives as Dopamine D₂ Receptor Partial Agonists: Design, Synthesis, and...

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-HT_2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D₂R partial agonists are effective as potential novel antipsychotics.