Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes.

Bartuzi D, Kędzierska E, Targowska-Duda KM, Koszła O, Wróbel TM, Jademyr S, Karcz T, Szczepańska K, Stępnicki P, Wronikowska-Denysiuk O, Biała G, Handzlik J, Kristensen JL, Poso A, Kaczor AA

Sci Rep 12 (1) 21192 [2022-12-07; online 2022-12-07]

Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

PubMed 36476619

DOI 10.1038/s41598-022-25478-7

Crossref 10.1038/s41598-022-25478-7

pmc: PMC9729218
pii: 10.1038/s41598-022-25478-7