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 (K_i = 0.22 nM) partial agonist (E_max = 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 (K_i = 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 (t_1/2 ≥ 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.