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.; Stępnicki, Piotr; Silva, Andrea G.; Koszła, Oliwia; Kędzierska, Ewa; Grudzińska, Angelika; Kruk-Słomka, Marta; Biała, Grażyna; Castro, Marián

doi:10.1016/j.neuint.2021.105016

Cited by 12 publications

(19 citation statements)

References 44 publications

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“…Atypical antipsychotics display anxiolytic activity based on 5-HT 2A receptor antagonism and 5-HT 1A receptor agonism or partial agonism. D2AAK1 13,14 has a complex effect on the anxiety processes, similarly as a previously reported compound D2AAK3 25 . Administration of D2AAK3 results in anxiogenic properties after 30 min and lack of the influence on anxiety-like behavior after 60 min.…”

Section: Discussionsupporting

confidence: 87%

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

Bartuzi

Kędzierska

Targowska-Duda

et al. 2022

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 87%

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

Bartuzi

Kędzierska

Targowska-Duda

et al. 2022

Sci Rep

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“…Motor coordination has been evaluated using the rota-rod test and the chimney test based on the same procedures as described previously. [19,23] Both tests were performed 60 min after injection of compounds 10 and 11 (1.5, 3, 6.25, 12.5, 25, and 50 mg/kg; i. p.) (n = 8) or vehicle (i. p.) (n = 12), using the same group of mice (i. e., after rota-rod test each mouse was placed to the chimney test).…”

Section: Animalsmentioning

confidence: 99%

“…The PA procedure was described previously. [18,23] To test the memory consolidation the animals received the injections of compounds 10 and 11 (3 mg/kg) or vehicle (control group) immediately after the test (on Day 1), and those rodents were retested on Day 2 (24 h later).…”

Section: Animalsmentioning

confidence: 99%

“…In case of most ligand-receptor complexes, Trp 6.48, Phe 6.51 and Phe 6.52 are key residues engaged in π-π stacking contact with N-benzyl moiety of the ligands as found for many similar complexes. [19][20][21]23,24] These residues, accompanied by His 6.55 constitute an aromatic microdomain of serotonin and dopamine receptors. [25] The orientation of the ligands in orthosteric binding pocket of the receptors is in accordance with our previous results.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…Control groups received injections (vehicle) at the same volume and by the same route of administration as previously reported. [19,23,24]…”

Section: Animalsmentioning

confidence: 99%

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Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety

et al. 2022

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Schizophrenia is a complex disease which is best treated with multitarget drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening, we found a virtual hit, D2AAK1, with nanomolar affinity for dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of an optimization campaign of D2AAK1, we obtained 17 derivatives that also display a multitarget profile. Selected compounds were tested against off-targets in schizophrenia, i. e., histamine H 1 receptor and muscarinic M 1 receptor, and these did not display considerable affinity for these receptors. The two most promising compounds were subjected to behavioral studies. These compounds decreased amphetamineinduced hyperactivity in mice which indicates their antipsychotic potential. The compounds did not interfere with the memory consolidation in mice, as determined in the passive avoidance test. The favorable pharmacological profile of these compounds was rationalized using molecular modeling.

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Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

Giorgioni,

Bonifazi,

Botticelli

et al. 2024

Medicinal Research Reviews

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Abstract5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered.

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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

Cited by 12 publications

References 44 publications

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

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

Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety

Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

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