Dopamine D<sub>3</sub>/D<sub>2</sub> Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders
Emma Gogarnoiu, Caleb D. Vogt, Julie Sanchez, Alessandro Bonifazi, Elizabeth Saab, Anver Basha Shaik, Omar Soler‐Cedeño, Guo‐Hua Bi, Benjamin Klein, Zheng‐Xiong Xi, J. Robert Lane, Amy Hauck Newman
Abstract
Highly selective dopamine D 3 receptor (D 3 R) 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 D 3 R partial agonist ( K i = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D 2 receptor (D 2 R). We hypothesized that compounds that are moderately D 3 R/D 2 R-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 D 3 R affinities ( K i = 0.14–50 nM) and moderate selectivity (<100-fold) over D 2 R. 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 D 3 R/D 2 R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.