In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic

Kaczor, Agnieszka A.; Targowska-Duda, Katarzyna M.; Budzyńska, Barbara; Biała, Grażyna; Silva, Andrea G.; Castro, Marián

doi:10.1016/j.neuint.2016.03.003

Cited by 36 publications

(61 citation statements)

References 66 publications

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“…Notably, a number of following docking studies reported in literature described a unique receptor cavity involved in the 5-HT 1A full agonists, partial agonists and antagonists binding [58][59][60], giving a further validation to our previous computational findings. Indeed, H-bond interactions between agonists and D116 and N386 were reported in literature, falling in a crevice delimited by F112, I113, D116, K191, while partial agonists as well as antagonists were Hbonded at least with D116.…”

Section: -Ht 1a R Docking-studiessupporting

confidence: 85%

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Franchini

Manasieva

Sorbi

et al. 2017

European Journal of Medicinal Chemistry

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Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HTR agonist with a moderate 5-HTR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HTR and α adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HTR partial agonists, the first being outstanding for selectivity (5-HT/α = 80), the latter for potency (pD = 9.58) and efficacy (E = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

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Section: -Ht 1a R Docking-studiessupporting

confidence: 85%

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Franchini

Manasieva

Sorbi

et al. 2017

European Journal of Medicinal Chemistry

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“…Chinese hamster ovary K1 (CHO-K1) cell lines stably expressing human D 2S , 5-HT 2A or H 1 receptors and human embryonic kidney 293 (HEK293) cell lines stably expressing human 5-HT 1A or 5-HT 7(a) receptors were in-house available [9][10][11], whereas CHO-K1 cell lines stably expressing human D 1 or D 3 receptors (Perkin Elmer, Waltham, MA, USA) and Chem-1 cell line stably expressing human M 1 receptor (Millipore, Merck KGaA, Darmstadt, Germany) were commercially available. Experimental conditions for binding assays at D 1 , D 2 , D 3 , 5-HT 1A and 5-HT 2A receptors have been previously reported [12]. 0.7 nM [ 3 H]-SCH23390, 2 nM [ 3 H]-SB269970 (5-HT 7 ), 2 nM [ 3 H]-Pyrilamine (H 1 ) and 2 nM [ 3 H]-Pirenzepine (M 1 ) were employed as radioligands.…”

Section: Receptor Binding Assaysmentioning

confidence: 99%

“…The efficacy of D2AAK4 as agonist or antagonist of D 2 receptors was evaluated in functional assays of cAMP signaling in the CHO-K1 cell line stably expressing the human D 2S receptor employed in radioligand binding assays, following a protocol already described [9,12]. Compound was initially assessed at 10 µM concentration either as agonist or as antagonist of 10 µM dopamine response.…”

Section: Functional Assay At D 2 Receptorsmentioning

confidence: 99%

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

et al. 2020

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N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity.

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“…2.9.1. Compound Preparation Compounds 1 and 2 were modeled using LigPrep module [23] of Schrödinger suite of software, v. 2019-4 as previously reported [24][25][26][27][28]. To identify the protonation state, Epik module [29] of Schrödinger suite of software, v. 2019-4 was applied.…”

Section: Molecular Modelingmentioning

confidence: 99%

2,4-Dichlorophenoxyacetic Thiosemicarbazides as a New Class of Compounds against Stomach Cancer Potentially Intercalating with DNA

et al. 2020

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Thiosemicarbazide is a useful structural moiety that has the biological potential. Optimization of this structure can result in groundbreaking discovery of a new class of therapeutic agents. In the light of this, 1-(2,4-dichlorophenoxy)acetyl-4-(1-naphthyl)thiosemicarbazide (1) and 1,4-bis[(2,4-dichlorophenoxy)acetylthiosemicarbazide]phenyl (2) were synthesized and characterized by spectroscopic method. Cytotoxicity of obtained compounds was evaluated on MKN74 gastric cancer cell line and human skin fibroblast BJ based on methylthiazolyldiphenyl-tetrazolium bromide (MTT) test. The apoptosis/necrosis and cell cycle analysis were conducted using image cytometry. Additionally, in DNA of treated cells, abasic sites (AP) and double strands breaks (DSB) presence were measured. Intercalating properties of active compounds were evaluated using the UV–spectroscopic method. Among newly synthesized derivatives, compound 2 showed toxic effects on gastric cancer cells with simultaneous lack of toxicity to normal fibroblasts. Cell cycle analysis revealed that both compounds influence cell division mainly at the stage of replication. Simultaneously with DNA synthesis disorders, DNA damages like AP-sites and DSBs were observed. Spectroscopic studies revealed possible DNA intercalating properties of tested compounds. Obtained results indicate that the newly synthesized thiosemicarbazide derivatives are a promising group of compounds with potential anticancer activity resulted from interactions with DNA and cell cycle interrupt.

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In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic

Cited by 36 publications

References 66 publications

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

2,4-Dichlorophenoxyacetic Thiosemicarbazides as a New Class of Compounds against Stomach Cancer Potentially Intercalating with DNA

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