Anticonvulsant effects of bis-1,4-dihydropyridines and the probable role of L-type calcium channels suggested by docking simulations

Juan, Eduardo Ramírez-San; Soriano-Ursúa, Marvin A.; Espinosa-Raya, Judith; Correa‐Basurto, José; Trujillo‐Ferrara, José G.; Miranda-Ruvalcaba, René; Delgado-Reyes, Francisco; Gómez-Pliego, Raquel

doi:10.1007/s00044-014-1083-0

Cited by 11 publications

(7 citation statements)

References 41 publications

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“…18 Anticonvulsant effect of 1,4 dihydropyridine (bis -DHP) has also been proved in male CF1 mice, on PTZ epileptic model. 19 The results of present study were in support of the previous studies, showing significant antiepileptic activity of NIMODIPINE, which significantly reduced the duration of THLE (p ˂0.001). Further, the potentiation of antiepileptic effect of PHENYTOIN was observed, when sub effective doses of Nimodipine and Phenytoin were combined.…”

Section: Discussionsupporting

confidence: 92%

Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

Raina

Jain

2018

Int J Basic Clin Pharmacol

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Background: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electroconvulsometer. In first part of study, animals were treated with Nimodipine (20mg/kg i.p. and 40mg/kg i.p.) and Phenytoin (0.5 mg/100g i.p. and 1.0mg/100g i.p.), MES was induced and durations of various phases were noted. Duration of Tonic hind limb extension (THLE) was taken as index for antiepileptic activity. In second part, the animals were treated with combination of sub effective doses of Nimodipine (20mg/kg i.p.) and Phenytoin (0.5mg/100g i.p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in dose dependent manner. Phenytoin produced significant antiepileptic effect in dose of 1.0mg/100g but failed to produce any such effect in dose of 0.5mg/100g, when administered alone. But when sub effective doses.Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusions: Nimodipine possess significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

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Section: Discussionsupporting

confidence: 92%

Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

Raina

Jain

2018

Int J Basic Clin Pharmacol

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“…[4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . …”

mentioning

confidence: 99%

“…[4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, [7][8][9] antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.…”

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confidence: 99%

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

El‐Moselhy

Sidhom

Esmat

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3-and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) 4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.Key words calcium channel; dihydropyridine; docking; synthesis; three-dimensional quantitative structureactivity relationship (3D-QSAR) Precise regulation of calcium homeostasis is crucial for many physiological functions.1) Divergent types of calcium channels and pumps can control the influx of calcium ions into cells.2,3) Consequently, targeting calcium channels is advantageously beneficial to yield useful drugs. Ca V 1.2 blockers can be roughly categorized into three different chemical classes: 1,4-dihydropyridine (DHP) derivatives, phenylalkylamine derivatives and benzothiazepine derivatives. Among them, DHP derivatives have the most significant pharmacological importance. For example, amlodipine is among the top-five best selling drugs in the treatment of cardiovascular diseases. Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . 20)Structure-activity relationship (SAR) of DHP 21) and the clinical usage of nifedipine have promoted us to synthesize two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking st...

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“…Hence, the target ligands were docked into the GABA A receptor structure, as reported by Muroi et al [ 28 ]. For the sodium channel open pore Nav1.2 study, we selected an open pore model that was developed based on the homology model of the crystal structures of potassium channels [ 29 ], prepared and validated as described elsewhere [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide

Garrido-Acosta

Meza‐Toledo

Anguiano‐Robledo

et al. 2016

BioMed Research International

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Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets—GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.

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Anticonvulsant effects of bis-1,4-dihydropyridines and the probable role of L-type calcium channels suggested by docking simulations

Cited by 11 publications

References 41 publications

Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide

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