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

Partial agonist activity at the dopamine D₂ 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_2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT_2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT_2AR 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_2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT_1AR with negligible 5-HT_2AR 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_1AR. This work indicates that 5-HT_2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.