Effect of N-(m-bromoanilinomethyl)-p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Abstract

The purpose of this study was to determine the effects of N-(m-bromoanilinomethyl)- p-isopropoxyphenylsuccinimide (BAM-IPPS - a new succinimide derivative) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the mouse maximal electroshock (MES)-induced tonic seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via ear-clip electrodes. BAM-IPPS administered (i.p.) at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). Lower doses of BAM-IPPS (50 and 100 mg/kg) had no significant impact on the threshold for electroconvulsions in mice. Moreover, BAM-IPPS (100 mg/kg) did not significantly affect the anticonvulsant potency of CBZ, PB, PHT and VPA in the mouse MES model. BAM-IPPS elevated the threshold for electroconvulsions in mice in a dosedependent manner. However, BAM-IPPS (100 mg/kg) did not affect the anticonvulsant action of various classical AEDs in the mouse MES model, making the combinations of BAM-IPPS with CBZ, PB, PHT and VPA neutral, from a preclinical point of view.

Anticonvulsant Potency of 10 Various P-Isopropoxyphenylsuccinimide Derivatives in the Maximal Electroshock-Induced Seizure Threshold Model in Mice

“…More specifically, no significant impairment of motor coordination (ataxia) or alleviation of skeletal muscular strength (flaccidity) were reported in mice [11][12][13][14][15][16][17][18]. In other words, lack of any adverse effects associated with the treatment with IPPS derivatives contributes to their favorable pharmacological profiles in preclinical studies.…”

“…To calculate the TID 20 values for IPPS derivatives, we used linear regression analysis, which analyzed the increasing doses of 10 IPPS derivatives and their corresponding threshold increases in mice challenged with the MEST test. It is important to note that the TID 20 values as determined in the MEST test are substantially lower than the experimentally determined ED 50 values in the MES test [11][12][13][14][15][16][17][18]. Furthermore, we have reported that some of the studied IPPS derivatives when combined with classical antiepileptic drugs, they potentiated the anticonvulsant properties of the selected antiepileptic drugs (i.e., phenytoin, phenobarbital and valproate) in the mouse MES model in mice [11,[13][14][15][16][17][18].…”

“…were tested in an in vivo experimental model of epilepsy -the maximal electroshock-induced seizure threshold (MEST) [11][12][13][14][15][16][17][18]. To unequivocally assess the anticonvulsant potency of the tested candidate drugs in the MEST model, the calculation of TID 20 value, i.e., doses of the compounds that increase the electroconvulsive threshold by 20% in drug-treated animals over the threshold in control animals, is recommended [19].…”

Microwave-promoted synthesis of cyclic imides

“…34 Substituted succinimides (3) such as ethosuximide, methosuximide or phensuximide, among others ( Figure 2), have strong anticonvulsant activity. 2,35,36 This type of imides, also have a variety of biological and pharmaceutical uses such as CNS depressant, analgesic, antitumor, cytostatic, anorexigenic, nerve conduction blocking, antispasmodic, bacteriostatic, muscle relaxant, hypotensive, antibacterial, antifungal and antitubercular. 2,37,38 Chiral succinimides with antifungal activity have shown higher activity than the corresponding racemic mixtures, thus opening new avenues for the development of highly active drugs containing 3-and 3,4-substituted chiral succinimides.…”

Effect of N-(p-ethoxycarbonylphenylmethyl) -p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

“…Accumulating evidence indicates that several succinimide derivatives have anticonvulsant properties in animal models of epilepsy [1,2,3,4,5,6,7,8,9,10]. More specifically, it has been reported that N-(anilinomethyl)p-isopropoxyphenylsuccinimide (AMIPPS) [2], N-pyridyl-substituted succinimides [3], N-(orthocarboxy anilinomethyl)-p-isopropoxyphenylsuccinimide (o-CAMIPPS), N-(meta-carboxyanilino-methyl)-p-isopropoxy phenylsuccinimide (m-CAMIPPS), and N-(paracarboxyanilinomethyl)-p-isopropoxyphenylsuccinimide (p-CAMIPPS) [4], 3-cyclohexyl-succinimides [5], N-morpho linemethyl derivative of m-bromophenylsuccinimide [6], p-iso-propoxyphenylsuccinimide monohydrate (IPPS) [7], N-hydroxymethyl-p-isopropoxy-phenyl-succinimide (HMIPPS) [8], N-(p-acetylphenyl)p-isopropoxyphenylsuccinimide (APIPPS) [9], N-morpholinomethyl-p-isopropoxyphenylsuccinimide (MMIPPS) [10], and 3-(N-p-isopropoxy-phenyl succini midomethylamino)-cinnamic acid (IPPSMA-CA) [11] exhibited potent anticonvulsant effects in the maximal electroshockinduced seizure (MES) test, recognized as the most widely employed animal seizure model for early identification of candidate anticonvulsant drugs [12,13]. In our pilot study, we found that N-(p-ethoxy carbonylphenylmethyl)-p-isopropoxyphenyl-succinimide (ECPM-IPPS) exerted anticonvulsant properties by suppressing tonic-clonic seizures in the mouse MES test (unpublished data).…”