Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Lifetime prevalence of psychotic and bipolar I disorders in a general population. This work indicates that 5-HT 2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT 1AR. 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 insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT 2AR and DRD2. 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’. Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT 2AR. However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine 5-HT) 2A receptor (5-HT 2AR). Partial agonist activity at the dopamine D 2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs).

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