Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
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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.
Originalsprog | Engelsk |
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Artikelnummer | 21192 |
Tidsskrift | Scientific Reports |
Vol/bind | 12 |
Udgave nummer | 1 |
Antal sider | 14 |
ISSN | 2045-2322 |
DOI | |
Status | Udgivet - 2022 |
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© 2022, The Author(s).
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