Dopamine D₃/D₂ Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders

Highly selective dopamine D₃ receptor (D₃R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D₃R partial agonist (K_i = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D₂ receptor (D₂R). We hypothesized that compounds that are moderately D₃R/D₂R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D₃R affinities (K_i = 0.14-50 nM) and moderate selectivity (<100-fold) over D₂R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D₃R/D₂R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.