Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties

Partial agonist activity at the dopamine D 2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT 2A R). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT 2A R. Both TGAs adopt an unexpected ‘upside-down’ pose in the 5-HT 2A R binding pocket, with secondary pharmacophores inserted in a similar way to a ‘bolt’. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT 2A R and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT 1A R with negligible 5-HT 2A R binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT 1A R. This work indicates that 5-HT 2A R affinity is a dispensable contributor to the therapeutic actions of TGAs. By solving the complex structures of third-generation antipsychotic drugs (TGAs) with the 5HT 2A receptor, Chen et al. unravel their unique pharmacology and design a novel TGA lead that has cognition-improving and potential antidepressant properties.