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

• Published in: Journal of medicinal chemistry Vol. 66; no. 3; pp. 1809 - 1834
• Main Authors: Gogarnoiu, Emma S., Vogt, Caleb D., Sanchez, Julie, Bonifazi, Alessandro, Saab, Elizabeth, Shaik, Anver Basha, Soler-Cedeño, Omar, Bi, Guo-Hua, Klein, Benjamin, Xi, Zheng-Xiong, Lane, J. Robert, Newman, Amy Hauck
• Format: Journal Article
• Language: English
• Published: American Chemical Society 09-02-2023
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01624

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.