Transformation of a Dopamine D₂ Receptor Agonist to Partial Agonists as Novel Antipsychotic Agents

Designed ligands of G protein-coupled receptors can exert a spectrum of modulating effects, varying from full agonists and partial agonists to antagonists and inverse agonists. For the dopamine D₂ receptor (D₂R), partial agonist activity is the pharmacological feature of the third-generation antipsychotics, including aripiprazole, brexpiprazole, and cariprazine. Started from a benzofuran-derived D₂R full agonist O₄LE₆ (4), which was identified using a structure-based method by us in previous studies, a series of D₂R partial agonists were designed and synthesized by introducing different tail groups. Among them, compound 10b showed excellent activity in D₂R pharmacological assays. Further optimizations using a structural rigidification approach led to the discovery of brain-penetrant compounds 29c and 29d, which exhibited potent antipsychotic effects in the mouse hyperlocomotion model. Compound 29c also showed excellent drug-like pharmacokinetic properties in rats and qualifies as an antipsychotic agent that is worth further evaluations.