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

Kaczor Agnieszka A.; Targowska-Duda Katarzyna M.; Stepnicki Piotr; Silva Andrea G.; Koszla Oliwia; Kedzierska Ewa; Grudzinska Angelika; Kruk-Slomka Marta; Biala Grazyna; Castro Marian

首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >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

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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

机译：n-（3- {4- [3-（三氟甲基）苯基]哌嗪-1-基}丙基）-1H-吲唑-3-甲酰胺（D2aak3）作为潜在的抗精神病药：体外，在硅和体内评估中多目标配体

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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.

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来源
《Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry》 |2021年第1期|共14页
作者
Kaczor Agnieszka A.; Targowska-Duda Katarzyna M.; Stepnicki Piotr; Silva Andrea G.; Koszla Oliwia; Kedzierska Ewa; Grudzinska Angelika; Kruk-Slomka Marta; Biala Grazyna; Castro Marian;
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作者单位

Med Univ Lublin Dept Synth &

Chem Technol Pharmaceut Subst Fac Pharm Comp Modeling Lab 4A;

Med Univ Lublin Dept Biopharm Fac Pharm 4A Chodzki St PL-20093 Lublin Poland;

Med Univ Lublin Dept Synth &

Chem Technol Pharmaceut Subst Fac Pharm Comp Modeling Lab 4A;

Univ Santiago de Compostela Dept Pharmacol Ctr Res Mol Med &

Chron Dis CIMUS Avda Barcelona E;

Med Univ Lublin Dept Synth &

Chem Technol Pharmaceut Subst Fac Pharm Comp Modeling Lab 4A;

Med Univ Lublin Dept Pharmacol &

Pharmacodynam Fac Pharm 4A Chodzki St PL-20093 Lublin Poland;

Med Univ Lublin Dept Synth &

Chem Technol Pharmaceut Subst Fac Pharm Comp Modeling Lab 4A;

Med Univ Lublin Dept Pharmacol &

Pharmacodynam Fac Pharm 4A Chodzki St PL-20093 Lublin Poland;

Med Univ Lublin Dept Pharmacol &

Pharmacodynam Fac Pharm 4A Chodzki St PL-20093 Lublin Poland;

Univ Santiago de Compostela Dept Pharmacol Ctr Res Mol Med &

Chron Dis CIMUS Avda Barcelona E;

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原文格式 PDF
正文语种 eng
中图分类生物化学;
关键词
Antipsychotics; Central nervous system diseases; Dopamine receptors; G protein coupled receptors; Schizophrenia; Serotonin receptors;

机译：抗精神病药;中枢神经系统疾病;多巴胺受体;G蛋白偶联受体;精神分裂症;血清素受体;

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机译：可能多巴胺D-4受体的无载体添加的2-（3-（4-（4- [F-18]氟苄基）哌嗪-1-基）丙基）苯并[d]噻唑的合成及体外评价放射性配体
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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

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