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

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.