Profile of Anticonvulsant Activity and Minimal Toxicity of Methyl 4‐[(p‐Chlorophenyl)amino]‐6‐Methyl‐2‐Oxo‐Cyclohex‐3‐En‐l‐Oate and Some Prototype Antiepileptic Drugs in Mice and Rats

Abstract

The anticonvulsant and toxic properties of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate (ADD 196022), were compared with those of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant testing procedures. Results indicate that ADD 196022 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses after intraperitoneal (i.p.) administration in mice and oral administration in rats. In mice, i.p. administration of ADD 196022 resulted in an ED50 value of 26.2 mg/kg as compared with a value of 6.48 mg/kg for PHT in the same assay. ADD 196022 was more potent that PHT in the oral rat model, having an ED50 value of 5.79 mg/kg as compared to 23.2 mg/kg for PHT. ADD 196022 was ineffective in nontoxic doses against all other seizure models evaluated and thus has a pharmacologic profile similar to that of PHT.

A Substituted Anilino Enaminone Acts as a Novel Positive Allosteric Modulator of GABAA Receptors in the Mouse Brain

“…Allosteric modulators of GABA A receptors such as benzodiazepines, neuroactive steroids, and barbiturates have been identified that are useful as anxiolytics, anticonvulsants, anesthetics, and sedative-hypnotics. Previous in vivo studies reported that enaminones show potent anticonvulsion effects in chemical-induced epilepsy animal models but fewer side effects such as sedation, drowsiness, and dizziness (Mulzac and Scott, 1993;Eddington et al, 2003). Based on these in vivo results and our results, we hypothesized and confirmed that KRS-5Me-4-OCF 3 binds to benzodiazepine sites to exert its pharmaceutical actions.…”

“…Previous in vivo studies reported that enaminones show potent anticonvulsion effects in chemical-induced epilepsy animal models but fewer side effects such as sedation, drowsiness, and dizziness (Mulzac and Scott, 1993;Eddington et al, 2003). Based on these in vivo results and our in vitro results, we hypothesized that KRS-5Me-4-OCF 3 might bind to ben- …”

“…This class of enaminones has shown good to moderate protection in the traditional preclinical animal models, the subcutaneous pentylenetetrazol test and the maximal electroshock seizure test. Their anticonvulsant activities are comparable with those of some clinically used agents in animal models of seizures with a minimal side effect profile as well as a wider margin of safety than conventional antiepileptic drugs such as carbamazepine, valproate, and phenytoin (Mulzac and Scott, 1993; This work was supported in part by the National Institute of Health National Institute of General Medical Sciences ; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant U54-NS039407]; and the Howard University New Faculty Research Program, the Howard University Health Sciences Faculty Seed Grant Program, the Whitehall Foundation.…”

“…The unique pharmacophoric structure of the anilino enaminones and the variety of bioactivities provide an excellent opportunity for developing new drugs. We reported previously the anticonvulsant activity of anilino enaminones in vivo and the possible mechanisms of action of these compounds by which they elicit their response (Edafiogho et al, 1992;Mulzac and Scott, 1993;Ananthalakshmi et al, 2007). The anilino enaminone E139 inhibited excitatory postsynaptic currents in the rat nucleus accumbens and hippocampus by enhancing extracellular GABA levels (Kombian et al, 2005;Ananthalakshmi et al, 2007) and inhibiting tetrodotoxin-sensitive sodium currents to modulate excessive firing in individual neurons .…”

Liquid chromatography‐tandem mass spectrometric method for determination of E121 in mouse plasma and its application to pharmacokinetics

“…The compounds were found to be effective for the treatment of generalized tonic-clonic and complex partial seizures in experimental animals comprising rats and mice [3][4][5]. More recently, enaminones, particularly E121, have also been shown to exert an antiinflammatory effect in a murine model of inflammation [6].…”