Activity In Maximal Electroshock Research Articles

Synthesis and anticonvulsant evaluation of semicarbazones of acetophenone Mannich bases

Several semicarbazones of acetophenone and p-chloroacetophenone Mannich bases were designed and synthesized to meet the pharmacophore requirements essential for anticonvulsant activity. Mannich bases of acetophenone and p-chloroacetophenone were prepared by reacting formaldehyde with various secondary amines and then condensed with several aryl semicarbazides to yield the corresponding semicarbazones. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES) and by subcutaneous metrazole (ScMet) and strychnine (ScSty) induced seizure methods, and their neurotoxic effects were determined using the rotorod test. The title compounds were also investigated for antidepressant and sedative-hypnotic potentiation properties. It is established that 3-[3-chlorophenyl(β-dimethylaminopropiophenone)semicarbazone] has excellent anticonvulsant activity in MES, ScSty, and ScMet tests and exhibits a potent antidepressant effect in the absence of sedative-hypnotic potentiation. The present study has proved our earlier hypothesis concerning the pharmacophore model with essential binding sites for semicarbazones. The inclusion of an additional moiety (CH2-CH2-N<) at the electron donor acceptor group retained the anticonvulsant activity.

Anticonvulsant and neurotoxicity evaluation of some 6-substituted benzothiazolyl-2-thiosemicarbazones

Various 6-substituted benzothiazolyl-2-thiosemicarbazones were synthesized and screened for anticonvulsant activity in maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. The 6-methyl benzothiazolyl-2-thiosemicarbazones showed anticonvulsant activity in both mice i.p. and rat oral MES screen. The 6-nitro benzothiazolyl thiosemicarbazone derivative 1a emerged as the most promising one with anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino derivatives had shown better activity when compared to the benzylidene or acetophenone derivatives.

Design, synthesis, and evaluation of analogues of 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide as orally available general anesthetics.

We have recently discovered a novel class of compounds that have oral general anesthetic activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure. Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds. Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a putative mechanism. Liposomal partitioning studies using (19)F NMR reveal that the aromatic region partitions into the core of the lipid. This partitioning correlated with general anesthetic activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM and slightly enhanced GABA(A) current in hippocampal neurons at 10 microM. Altogether, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).

EFFECT OF PROPRANOLOL AND NIFEDIPINE ON MAXIMAL ELECTROSHOCK-INDUCED SEIZURES IN MICE: INDIVIDUALLY AND IN COMBINATION

A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kg−1on maximal electroshock (MES)-induced seizure in mice was investigated. Propranolol in doses of 10 mg kg−1and 20 mg kg−1, and nifedipine in doses of 8 mg kg−1and 16 mg kg−1significantly modified MES activity. Propranolol (40 mg kg−1), and a combination of propranolol (20 mg kg−1) and nifedipine (8 mg kg−1), produced antiMES activity, which was comparable to that of phenytoin (30 mg kg−1). In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios (F/E ratio) were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice.

Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid derivatives that are antagonists at the NMDA-associated glycine binding site.

Twelve 4-urea-5,7-dichlorokynurenic acid derivatives were synthesized by reacting the 4-tosylimino derivative of 5,7-dichlorokynurenate methyl ester first with triphosgene and then with a secondary amine. Compounds were screened in mice for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole (Met), and threshold tonic extension (TTE) tests. A rotorod test was used to determine neurotoxicity. Seven of the derivatives had anticonvulsant activity in TTE testing at 100 mg/kg. One compound, 2-methyl carboxylate-5,7-dichloro-4-([¿diphenylamino¿-carbonyl]amino)-quino line, had an ED50 value of 134 mg/kg (95% conf. int.: low-78.5, high-205.7; slope 1.9, SE = 0.44) in TTE testing. Two derivatives had MES activity. Only one compound, an N,N-diethylamino derivative, was neurotoxic in the rotorod test. Compounds were screened at a 10-microM concentration for activity in displacing 5,7-dichlorokynurenic acid from synaptosomal membrane fragments. Since 9 of the 12 compounds synthesized and tested have demonstrated anticonvulsant activity, this class of chemicals offers promise for the production of useful therapeutic agents.

Parenteral magnesium sulfate fails to control electroshock and pentylenetetrazol seizures in mice

Magnesium sulfate has been used as an anticonvulsant in the treatment of eclampsia, but efficacy of magnesium in other types of seizure disorders is poorly documented. We examined the effects of magnesium sulfate (MgSO 4) on seizures produced in mice by maximal electroshock (MES) and pentylenetetrazol (PTZ). MgSO 4 injection (6.7 mEq/kg i.p.) caused weakness in all animals. With supra-threshold electroshock, 10 10 controls and 11 12 treated animals had seizures with tonic hind limb extension ( P = NS). Electroshock threshold was unaltered by magnesium treatment ( n = 48; P = 0.47). PTZ induced clonic seizures in 12 12 controls and 5 14 treated animals ( P < 0.05). This difference was likely due to muscular weakness because frequency of EEG spikes was the same in PTZ and PTZ + MgSO 4 groups. Mean serum magnesium levels were 2.3 ± 0.3 mEq/1 in animals not given MgSO 4; 10.9 ± 1.4 mEq/1 and 12.8 ±2. mEq/1 in treated animals with and without seizures ( P = NS). We conclude that magnesium sulfate had no significant anticonvulsant activity in mouse MES and PTZ models for epilepsy. The relevance of these findings to the possible efficacy of magnesium sulfate in eclamptic seizures and other types of epilepsy remains to be determined.