Design, anticonvulsive and neurotoxic properties of retrobenzamides. N-(Nitrophenyl)benzamides and N-(aminophenyl)benzamides.

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.

Anticonvulsant and neurotoxicological properties of 4-amino-N-(2-ethylphenyl)benzamide, a potent ameltolide analogue.

A well documented study on the anticonvulsant properties of 4-amino-N-(2-ethylphenyl)benzamide (4-AEPB) is here provided. Initial screening in mice dosed intraperitoneally and rats dosed orally indicated that 4-AEPB is active against maximal electroshock-induced seizures (MES), but does not protect animals against subcutaneous pentylenetetrazole (sc Ptz)-induced seizures. Quantitative evaluation of anti-MES activity and neurotoxicity of 4-AEPB given intraperitoneally to mice provided ED50 and TD50 values amounting to 28.6 and 96.3 mumol/kg respectively, resulting in a protective index (PI = TD50/ED50) equal to 3.36. Further quantitative evaluation in rats dosed orally indicated that the respective ED50 and TD50 values for 4-AEPB were 29.8 and more than 1,530 mumol/kg, resulting in a very high PI value of over 51. Comparison anticonvulsant properties and neurotoxicity of 4-AEPB with those previously reported in the literature for two 4-aminobenzamide derivatives, 4-amino-N-(2,6-dimethylphenyl)benzamide (or ameltolide, an antiepileptic drug prototype developed by Eli Lilly), and phenytoin, underlines the value of 4-AEPB for future pharmacological development. In this perspective, an additional favorable element is represented by the ability of 4-AEPB to increase the seizure threshold in the intravenous Ptz seizure threshold test in mice dosed intraperitoneally. Molecular modeling studies show that the translocation of one carbon unit in the isomerization of the 2,6-dimethylphenyl moiety of ameltolide to the 2-ethylphenyl counterpart succeeds in maintaining the conformational low energy presentation adopted by ameltolide, providing clues as to why the 4-AEPB here described is an anticonvulsant agent derived from the 4-aminobenzamide pharmacophore platform as potent as ameltolide.

[Rational conception, synthesis and evaluation of phenytoinergic potential anticonvulsants. A series ofretrobenzamides: N-(nitrophenyl) benzamides and N-(aminophenyl) benzamides]. / Conception rationnelle, synthèse et évaluation d'agents anticonvulsivants originaux à potentialité phénytoïnergique. La série des rétrobenzamides: les N-(nitrophényl) benzamides et les N-(aminophényl)benzamides.

Retrobenzamides [N-(nitrophenyl) benzamides and N-(aminophenyl)benzamides] were developed in the perpective of a design for phenytoinergic agents. Anticonvulsant and neurotoxic properties of these compounds were evaluated in mice and rats in two seizure models (maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentylenetetrazole [scPtz]) and in the rotorod test. Data obtained were compared with those recorded on carbamazepine and phenytoin (antiepileptic drugs widely utilized in human clinics), ameltolide (anticonvulsant compound recently developed by Eli Lilly in human clinical trials) and other compounds previously reported by our research group. Studies on retrobenzamides in mice administered by intraperitoneal route point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity in the case of the corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were less active in the MES test than in mice dosed intraperitoneally.

Increase in cytochrome oxidase capacity of BAT and other tissues in cold-acclimated gerbils.

To determine the effects of cold acclimation on the oxidative capacity of different tissues and their possible role in nonshivering thermogenesis (NST) in a desert rodent, the gerbil (Gerbillus campestris), measurements of cytochrome oxidase activity (COX) were performed on homogenates of liver, brown adipose tissue (BAT), and subsarcolemmal (SS) and intermyofibrillar (IMF) fractions of skeletal muscle. Total organ mass was also measured. Gerbils were maintained either at thermoneutrality (TN) or cold [4 degrees C, ambient temperature (Ta)] for 4 (CA4) or 8 (CA8) wk. A comparative study was made with mice (Mus musculus). Total and relative masses of BAT increased significantly in both gerbils and mice during cold acclimation, whereas muscle mass decreased in CA4 gerbils. Specific and total COX (TCOX) increased in the three tissues. A considerable increase (+170%, P less than 0.05) of TCOX and protein content in liver of CA4 gerbils compared with controls was observed, whereas no significant changes occurred in liver of CA4 mice. In muscle, an increase of TCOX in SS and a reduction in IMF cell compartments were noted. The increase in BAT oxidative capacity in CA4 gerbils represented only a small portion of that in liver (36%) and in SS fraction of muscle (41%) at the same stage of acclimation. The ability of the three tissues to contribute to components of thermogenesis in vivo was evaluated. The sum of oxidative capacity of the three tissues was largely above the peak metabolic rate (PMR), whereas that of muscle exceeded maximum shivering thermogenesis, which developed both in TN and CA4 gerbils.(ABSTRACT TRUNCATED AT 250 WORDS)