Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
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Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes. / 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.
In: Scientific Reports, Vol. 12, No. 1, 21192, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
AU - Bartuzi, Damian
AU - Kędzierska, Ewa
AU - Targowska-Duda, Katarzyna M.
AU - Koszła, Oliwia
AU - Wróbel, Tomasz M.
AU - Jademyr, Simon
AU - Karcz, Tadeusz
AU - Szczepańska, Katarzyna
AU - Stępnicki, Piotr
AU - Wronikowska-Denysiuk, Olga
AU - Biała, Grażyna
AU - Handzlik, Jadwiga
AU - Kristensen, Jesper L.
AU - Poso, Antti
AU - Kaczor, Agnieszka A.
N1 - Funding Information: The research was funded under OPUS grant from National Science Center (NCN, Poland), Grant Numbers 2017/27/B/NZ7/01767 and UMO-2021/43/B/NZ7/01732 (to A.A.K). Calculations were performed under PRACE European Computing Infrastructure Grants MOLTRANSREC and NERVOMOLSIM (to A.A.K.), Poznań Supercomputing and Networking Center Grant MOLTRANSREC (to A.A.K.), Interdisciplinary Center for Mathematical and Computational Modeling in Warsaw grant, Grant Number G85-948 (to A.A.K) and under resources of CSC Finland. The work was supported by Polish National Agency for Academic Exchange within the Bekker NAWA Programme, project PANALLOS, Grant Number BPN/BEK/2021/1/00408/U/00001 (to D.B.).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-022-25478-7
DO - 10.1038/s41598-022-25478-7
M3 - Journal article
C2 - 36476619
AN - SCOPUS:85143558153
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 21192
ER -
ID: 329198692