Featured Paper of the Month – July 2023
Cocaine and methamphetamine are highly addictive psychostimulants that continue to challenge the health and well-being of those who develop a psychostimulant use disorder (PSUD). To date, there are no FDA approved medications for the treatment of PSUD and this provides a significant challenge to curb its destructive nature and prevent death by overdose. Highly selective dopamine D3 receptor (D3R) partial agonists and antagonists have been developed for the treatment of 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-preferential partial agonist that may have potential for treating PSUD. However, cariprazine’s dopamine D2 receptor (D2R) activity may not be well tolerated in people with PSUD. In this report, we systematically modified the chemical structure of cariprazine and discovered partial agonists with high D3R affinities (Ki = 0.14–50 nM) and moderate selectivities (10-100-fold) over D2R. Cariprazine and two lead analogues decreased cocaine self-administration (FR2; 1–10 mg/kg, i.p.) in rats, supporting our hypothesis that partial agonists with modest D3R/D2R-selectivity may be effective in treating PSUD and may also be effective in treating patients who have comorbidities with other affective disorders.
In: Journal of Medicinal Chemistry, vol. 66, no. 3, pp. 1809–1834, 2023, ISBN: 0022-2623.