RT Journal Article
T1 N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand
A1 Kaczor, Agnieszka A.
A1 Targowska-Duda, Katarzyna M.
A1 Stępnicki, Piotr
A1 Silva, Andrea G.
A1 Koszła, Oliwia
A1 Kędzierska, Ewa
A1 Grudzińska, Angelika
A1 Kruk-Słomka, Marta
A1 Biała, Grażyna
A1 Castro Pérez, María de los Ángeles
K1 Antipsychotics
K1 Central nervous system diseases
K1 Dopamine receptors
K1 G protein coupled receptor
K1 Schizophrenia
K1 Serotonin receptors
AB Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.
PB Elsevier Ltd.
SN 0197-0186
YR 2021
FD 2021-03-17
LK https://hdl.handle.net/10347/39504
UL https://hdl.handle.net/10347/39504
LA eng
NO Kaczor AA, Targowska-Duda KM, Stępnicki P, Silva AG, Koszła O, Kędzierska E, Grudzińska A, Kruk-Słomka M, Biała G, Castro M. N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand. Neurochem Int. 2021 Jun;146:105016
DS Minerva
RD 29 abr 2026