7vod

Publication Abstract from PubMed

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-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR 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-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR 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-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.,Chen Z, Fan L, Wang H, Yu J, Lu D, Qi J, Nie F, Luo Z, Liu Z, Cheng J, Wang S Nat Neurosci. 2021 Dec 9. pii: 10.1038/s41593-021-00971-w. doi:, 10.1038/s41593-021-00971-w. PMID:34887590^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.