Computational studies on α-aminoacetamide derivatives with anticonvulsant activities (original) (raw)
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ACS chemical neuroscience, 2011
We recently reported that merging key structural pharmacophores of the anticonvulsant drugs lacosamide (a functionalized amino acid) with safinamide (an α-aminoamide) resulted in novel compounds with anticonvulsant activities superior to that of either drug alone. Here, we examined the effects of six such chimeric compounds on Na(+)-channel function in central nervous system catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that these compounds affected Na(+) channel fast and slow inactivation processes. Detailed electrophysiological characterization of two of these chimeric compounds that contained either an oxymethylene ((R)-7) or a chemical bond ((R)-11) between the two aromatic rings showed comparable effects on slow inactivation, use-dependence of block, development of slow inactivation, and recovery of Na(+) channels from inactivation. Both compounds were equally effective at inducing slow inactivation; (R)-7 shifted the fast inacti...
Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants
Bioorganic & Medicinal Chemistry Letters, 1999
Sodium channel blocking, anticonxatlsant activity, and sigma (or) binding of selected leads in a series of ctamino amide anticonvulsants were examined. While anticonvulsant compounds were always endowed with low micromolar sodium (Na +) channel site-2 binding, compounds with low site-2 Na + channel affirfity failed to control seizures. No correlation could be drawn with ol binding. Both anticonvulsant and Na + channel blocking activities were independent of stereochemistry, while ~1 binding seems to be favoured by an S-configuration on the aminoanude moiety.
Egyptian Journal of Basic and Applied Sciences, 2017
This research studied the anticonvulsant properties of three synthesized isomers of dichloro-substituted phenyl amino propanamides in rodents and determined their effects on votage-gated sodium channels (Na V 1.6) stably expressed in Human Embryonic Kidney (HEK Cells 293). 2,3-, 2,5-and 3,4-Dichloro anilines were reacted with acrylamide according to Michael-type addition reaction to obtain their corresponding isomers; DCP23, DCP25 and DCP34. Each isomer was evaluated for anticonvulsant effects using maximal electroshock (MES)-and pentylenetetrazole (PTZ)-induced seizure models in mice; tested against PTZ-induced kindling in rats and its synergistic effect with fluphenamic acid in mice. Effects of DCP23 and DCP25 were studied on voltage-gated sodium channels (Na V 1.6) at different states of the channel, using electrophysiology techniques. The test compounds generally offered dose dependent protection against maximal electroshock-and pentylenetetrazole (PTZ)-induced seizure; demonstrated synergistic effect when co-administered with fluphenamic acid; and produced significant (p < 0.05) decrease in seizure progression in PTZ-kindled rats. DCP23 and DCP25 reduced sodium currents at different channel states in a concentration dependant manner. The results of this study showed that the compounds possess anticonvulsant effects and reduced the inward sodium currents. Therefore, they could exert anticonvulsant activity via sodium channels blockade.
The Structure-Activity Relatıonships of Familiar Antiepileptic Drugs and Na+ Channels
Hittite Journal of Science and Engineering
The aim of this study is to examine the effects of drug active compounds, which are widely used in the treatment of epilepsy, on voltage-gated Na+ channels are important channels that advance the action potential in the excitation direction by molecular docking method. These molecules have been selected considering the physiopathological effect mechanisms of epilepsy disease. When the action potential is stimulated, Na+ channels allow sodium ion entry into the cell and cause epilepsy seizures. For this reason, PDB ID: 4PA6 receptor, which acts as an antagonist according to its activity on the canal in the formation of epileptic seizures, was chosen for molecular docking study. As a result of molecular docking studies; Phenytoin gave the best binding affinity for 4PA6 with a value of -7.7 kcal/mol. Other results in descending order (as kcal/mol); Mesuximide (-7.5), Remasemide (-7.3), Tiagabine (-7.1), Ethotoin and Mephenytoin (-7.0), Primidon (-6.9), Topiramate (-6.6), Oxcarbazepine ...
Brain Research, 1993
U-54494A, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide, has been shown to be a potent and long-acting anticonvulsant without analgesic or sedative effects on intact animals. The persistence of anticonvulsant activity after a decline in its concentration in the brain 9 implies the conversion of the parent drug into active metabolites. In this study, two major metabolites of U-54494A, U-83892E [cis-N-(2aminocyclohexyl)-3,4-dichlorobenzamide] and U-83894A [cis-N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide], were identified. The synthetic metabolites displayed anticonvulsant activity against electric shock in experimental animals and blocked voltage-gated sodium channel in N1E-115 neuroblastoma cells in voltage-and use-dependent manner by interacting with the inactivated channels as well as with the channels in the resting state (like the parent compound). These observations may provide one explanation for the long duration of the anticonvulsant activity of the parent compound U-54494A and further underscore the importance of voltage-dependent sodium channels in neuronal excitability, especially during seizures.
Neuropharmacology, 2007
Phenytoin (DPH) is a clinically useful sodium (Na) channel blocker with efficacy against partial and generalized seizures. We have developed a novel hydantoin compound (HA) using comparative molecular field analysis (CoMFA) and evaluated its effects on hNa v 1.2 channels. Both DPH and HA demonstrated affinity for resting (K r = 13.9 µM for HA, K r = 464 µM for DPH) and slow inactivated channels (K I = 975 nM for HA, K I = 20.6 µM for DPH). However, HA also exhibited an affinity for fast inactivated channels (K I = 2.5 µM) and shifted the V 1/2 for activation in the depolarizing direction. Furthermore, HA exhibited profound use dependent block at both 5 and 10 Hz stimulation frequencies. In the 6 Hz seizure model (32 mA) HA had an ED 50 of 47.1 mg/kg and a TD 50 of 131 mg/kg (Protective Index (P.I.) = 2.8). In comparison, the ED 50 for DPH was ~27.5 mg/kg with a TD 50 of 35.6 mg/kg (P.I. ~ 1.3). These findings provide evidence for the utility of CoMFA in the design of novel anticonvulsant and support the hypothesis that selectivity plays an important role in achieving optimal protection with minimal side effects.
2018
Quantitative Structure-Activity Relationship (QSAR) modeling was conducted on some 3-aminopropane-1, 2-diol and 1-aminoethane-1, 2-diol derivatives with anticonvulsant activity against maximal electroshock induced seizure using Genetic Function Algorithm-Multiple Linear Regression (GFA-MLR) method. The data set (37 molecules), was divided into 26 training and 11 test subsets by Modified-K-mediods clustering method. The models built by the GFA-MLR method provided satisfactory statistical results with LOF (0.087 to 0.097), R 2 (0.963 to 0.980), Q 2 (0.948 to 0.971), F (139.3 to 258.3), R 2 pred (0.861 to 0.931) and MAE (95%) (0.059 to 0.066). Descriptors contained in these models suggested that increment in molecular mass and polarizability of dataset molecules was favorable for improving their anticonvulsant activity values. Intelligent consensus modeling applied to the models gave a representative model with improved MAE (95%) of 0.054. Applicability domain of the models was well defined and therefore, the models can be used to screen molecules for anticonvulsant activity.
Epilepsy is a common brain disease that is characterized by recurrent and spontaneous seizures that result from abnormal and excessive synchronization of neuronal activity. Whereas, accumulation of Ca++ in presynaptic terminals, leading to improved neurotransmitter release. In additional, depolarization-induced inauguration of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca++ influx and neuronal activation. The main aim of this study to focus on the deactivation of Ca++ influx and prevent the augmentation of neuron activation. However, we performed molecular modeling of novel 1,3,4-thiadiazole derivatives keeping in view structural requirement of pharmacophore and Quantitative structure activity relationship (QSAR) and evaluated in silico anticonvulsant activity. Docking procedures allow virtually screening a database of compounds and predict the strongest binder based on various scoring functions. In the docking study, targeted ligand produced significantly affinity with the calcium channel receptor which is slightly higher than the phenytoin drug. A computational study was also carried out including prediction of pharmacokinetic properties, toxicity and bioactivity studies. All above parameter was calculated which exhibited slightly excellent compared than standard Phenytoin drug. The above observation suggested that these compounds would serve as better lead for anticonvulsant screening for future drug design perspective.
European journal of pharmacology, 2018
In patients with epilepsy, anxiety and depression are the most frequent psychiatric comorbidities but they often remain unrecognized and untreated. We report herein the antidepressant-like activity in two animal models, tail suspension and forced swimming tests, of six anticonvulsants α-hydroxyamides. From these, N-propyl-2,2-diphenyl-2-hydroxyacetamide (compound 5) emerged not only as the most active as anticonvulsant (ED = 2.5mg/kg, MES test), but it showed the most remarkable antidepressant-like effect in the tail suspension and forced swimming tests (0.3-30mg/kg, i.p.); and, also, anxiolytic-like action in the plus maze test (3-10mg/kg, i.p.) in mice. Studies of its mechanism of action, by means of its capacity to act via the GABA receptor ([H]-flunitrazepam binding assay); the 5-HT receptor ([H]-8-OH-DPAT binding assay) and the voltage-gated sodium channels (either using the patch clamp technique in hNa 1.2 expressed in HEK293 cell line or using veratrine, in vivo) were attempt...