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

• Published in: Scientific reports Vol. 12; no. 1; pp. 21192 - 14
• Main Authors: Bartuzi, Damian, Kędzierska, Ewa, Targowska-Duda, Katarzyna M, Koszła, Oliwia, Wróbel, Tomasz M, Jademyr, Simon, Karcz, Tadeusz, Szczepańska, Katarzyna, Stępnicki, Piotr, Wronikowska-Denysiuk, Olga, Biała, Grażyna, Handzlik, Jadwiga, Kristensen, Jesper L, Poso, Antti, Kaczor, Agnieszka A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 07.12.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Allosteric properties; Antipsychotics; Anxiety; Behavior; Coronaviruses; COVID-19; Dopamine; Drug dosages; Humans; Laboratories; Ligands; LSD; Lysergic acid diethylamide; Lysergide; Mental disorders; Pharmaceuticals; Pharmacy; Psychedelic drugs; Psychotropic drugs; Schizophrenia; Serotonin; Serotonin S1 receptors; Serotonin S2 receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-25478-7

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-HT 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-HT and 5-HT 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-5HT R 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.