Synthesis, biological evaluation and structure–activity relationship of new GABA uptake inhibitors, derivatives of 4-aminobutanamides

Kowalczyk, Paulina; Sałat, Kinga; Höfner, Georg; Mucha, Marta; Rapacz, Anna; Podkowa, Adrian; Filipek, Barbara; Wanner, Klaus T.; Kulig, Katarzyna

doi:10.1016/j.ejmech.2014.06.024

Cited by 16 publications

(10 citation statements)

References 48 publications

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“…Forty-five minutes before pilocarpine, animals were also pretreated with scopolamine butylbromide (1 mg/kg, i.p.) to reduce peripheral autonomic side effects and masticatory and stereotyped movements (Kowalczyk et al 2014 ). Direct observation was performed for 60 min to monitor the latency time to the onset of the limbic seizures, characterized by a subsequent development of behavioral symptoms, such as tremor, head bobbing, and myoclonic movements of the forelimbs progressing to recurrent myoclonic convulsions with rearing, salivation, falling, and status epilepticus (Łuszczki et al 2008 ; Turski 2000 ).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione

Rapacz

Rybka

Obniska

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.

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Section: Methodsmentioning

confidence: 99%

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione

Rapacz

Rybka

Obniska

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Hence, in this study 65 selected mouse models of seizures, acute and tonic pain, anxiety 66 and depression were used to assess pharmacological profile of this 67 drug. [13]. Clonic seizures were induced by a subcutaneous 92 (sc) injection of PTZ at the dose of 100 mg/kg.…”

mentioning

confidence: 99%

Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression

Sałat

Podkowa

Kowalczyk

et al. 2015

Pharmacological Reports

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“…24,25 PC12 cell is also the main cell system used in the discovery and development of bio-active chemicals for the treatment of AD. 26,27 In this study, the activity of QC and generation of pE-Aβ in PC12 cells were both obviously inhibited after the culture with 23. Data obtained here supported the action of QC inhibitor to reduce the generation of pE-Aβ by inhibiting QC activity in a cell system.…”

Section: Regulates Ribosome In Pc12 Cellsmentioning

confidence: 55%

“…As a cloned line of rat pheochromocytoma cells, PC12 cells contain many membrane‐bound and cytosolic molecules associated with neurons, responds to nerve growth factor (NGF) by cessation of division, and extension of neurone‐like processes and has been widely used in the differentiation of neurone, pathological and physiological research related with AD and other neurodegenerative diseases as a cell model . PC12 cell is also the main cell system used in the discovery and development of bio‐active chemicals for the treatment of AD . In this study, the activity of QC and generation of pE‐Aβ in PC12 cells were both obviously inhibited after the culture with 23 .…”

Section: Discussionmentioning

confidence: 99%

Glutaminyl cyclase inhibitor contributes to the regulation of HSP70, HSP90, actin, and ribosome on gene and protein levels in vitro

Zou

et al. 2018

J of Cellular Biochemistry

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Because of the crucial roles of upregulated glutaminyl cyclase (QC) in the initiation and development of Alzheimer's disease (AD), QC inhibitors are supposed as disease-modifying agents for the treatment of AD. And reported compounds encourage this hypothesis greatly based on the remarkable anti-AD effects in vivo. To illustrate the mechanism in detail, the actions of a selected QC inhibitor (23) were assessed firstly in a cell system here. It was demonstrated that QC activities and the generation of pyroglutamate-modified β-amyloids in PC12 cells were both inhibited obviously after the treatment of 23.A total of 13 and 15 genes were up-and downregulated significantly in treated cells by RNA-sequencing analysis. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, WB, and immunofluorescence analysis supported the effects of 23 on the transcriptome of PC12 cells consequently. The expressions of chaperones, heat shock proteins (HSP) 70, and 90, were upreglutated, while gene expression of actin and the level of encoded protein were reduced significantly in PC12 cells with the treatment.Furthermore, the regulations of ribosome were observed after the treatment. These results indicate the potency of 23 to improve the translation, expression and folding regulation of proteins and affect the multivalent cross-linking of cytoskeletal protein and other proteins subsequently in the cell system and might contribute to the understanding of the mechanism of QC inhibitor as potential anti-AD agents.

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Synthesis, biological evaluation and structure–activity relationship of new GABA uptake inhibitors, derivatives of 4-aminobutanamides

Cited by 16 publications

References 48 publications

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione

Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression

Glutaminyl cyclase inhibitor contributes to the regulation of HSP70, HSP90, actin, and ribosome on gene and protein levels in vitro

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