Tailoring cariprazine for dual disorders via secondary pharmacophore optimization.

Cariprazine is an approved drug used to treat schizophrenia, bipolar disorder, and (more recently) major depression. These serious mental illnesses are often comorbid with psychostimulant use disorders, for which no pharmacotherapeutic is currently approved. Based on preclinical data and multiple case studies, cariprazine demonstrates significant potential as a treatment for such dual disorders. Notably, this drug acts as a high-affinity (Ki = 0.22 nM) partial agonist (Emax = 45.1%) of the dopamine D3 receptor (D3R), a molecular target implicated in a variety of substance use disorders. Unlike other atypical antipsychotics, cariprazine is 3.6-fold more selective for D3R than the homologous dopamine D2 receptor (D2R). Because patients with psychostimulant use disorders may be more susceptible to D2R-related side effects, we hypothesized that compounds with a higher D3R selectivity may offer a therapeutic advantage over cariprazine. By modifying part of the parent drug structure (i.e., secondary pharmacophore), analogues were developed that bind to D3R with similar affinity (Ki = 0.248-2.97 nM) and improved selectivity over D2R (5.0- to 39-fold). Compared to cariprazine, these derivatives behaved functionally as D3R partial agonists and retained a similar off-target profile; however, the most promising compounds also exhibited improved metabolic stability in rat liver microsomes (t1/2 ≥ 61.3 min). Taken together, our findings support further study of the lead candidate (8) for treating dual disorders that may have a reduced side effect profile.