[Propranolol and lactatemia during hypovolemic shock: a case report]. / Propranolol et lactatémie durant un choc hypovolémique non septique : à propos d'une observation.

Lactate production results from anaerobic glycolysis. This pathway is recruited physiologically during intense and sustained muscular contractions. Hyperlactatemia may develop when tissue oxygenation is jeopardized such as in shock, its absence having been, however, sometimes reported in sepsis in which interactions between infectious agents and the organism's cells might blunt or disrupt hyperlactatemia development. During the course of acute rotavirus gastroenteritis, a 9-month-old girl developed severe dehydration (capillary-refill time, 5 s) leading to hypovolemic shock without signs of sepsis and with hypotension at 62/21 mmHg Surprisingly, the child failed to develop hyperlactatemia during shock. An etiologic search to understand why hyperlactatemia did not occur revealed that this patient had been receiving propranolol since the age of four months for the treatment of a Cyrano hemangioma. Via its inhibitory action on ß-adrenergic receptors, propranolol antagonizes the stimulation of glycolysis by catecholamines, which may be rationally proposed to have contributed to preventing hyperlactatemia during hypovolemic shock in this patient. Mechanisms by which propranolol can mediate this antihyperlactatemia action are further illustrated and discussed.

Genetic-dependency of peroxisomal cell functions - emerging aspects.

This paper reviews aspects concerning the genetic regulation of the expression of the well studied peroxisomal genes including those of fatty acid beta-oxidation enzymes; acyl-CoA oxidase, multifunctional enzyme and thiolase from different tissues and species. An important statement is PPARalpha, which is now long known to be in rodents the key nuclear receptor orchestrating liver peroxisome proliferation and enhanced peroxisomal beta-oxidation, does not appear to control so strongly in man the expression of genes involved in peroxisomal fatty acid beta-oxidation related enzymes. In this respect, the present review strengthens among others the emerging concept that, in the humans, the main genes whose expression is up-regulated by PPARalpha are mitochondrial and less peroxisomal genes. A special emphasis is also made on the animal cold adaptation and on need for sustained study of peroxisomal enzymes and genes; challenging that some essential roles of peroxisomes in cell function and regulation still remain to be discovered.

A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.

FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.

Antioxidant actions of ovothiol-derived 4-mercaptoimidazoles: glutathione peroxidase activity and protection against peroxynitrite-induced damage.

4-Mercaptoimidazoles derived from the naturally occurring antioxidants, ovothiols, were tested for their glutathione peroxidase-like (GSH Px-like) activity and protection against peroxynitrite-induced damage. All the thiol compounds displayed similar significant GSH Px-like activities, which are however weaker than that of the reference compound, ebselen. The inhibitions of the peroxynitrite-dependent oxidation of Evans blue dye and dihydrorhodamine 123 showed that the thiol compounds substituted on position 5 of the imidazole ring were nearly as effective as ebselen while the C-2 substituted ones were less effective. Both assays corroborate the large superiority of mercaptoimidazoles over glutathione as inhibitors of peroxynitrite-dependent oxidation.

Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction.

Disorders of neuronal migration in cerebral cortex are associated with neurological impairments, including mental retardation and epilepsy. Their causes and pathophysiology remain largely unknown, however. In patients with Zellweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration. Analysis of Pxr1-/- mice revealed that the migration defect was caused by altered N-methyl-D-aspartate (NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenomenon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome metabolism and NMDA receptor efficacy.

Evolutionary aspects of peroxisomes as cell organelles, and of genes encoding peroxisomal proteins.

Peroxisomes are present in most eukaryotic cell types, and have different enzymatic content and metabolic functions throughout the life scale. The endosymbiotic origin of these DNA-devoid organelles is supported by evolutionary data concerning genes encoding not only most peroxisomal proteins, but also several transcriptional factors regulating their expression such as peroxisome proliferator-activated receptors.

Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore.

A series of compounds including 4-amino (1), 3-amino (2), 4-nitro (3), 2-methyl-3-amino (4), 2-methyl-3-nitro (5), 2-methyl-4-amino (6), 2-methyl-4-nitro (7), 2-methyl-5-amino (8), 2-methyl-5-nitro (9), 2-methyl-6-amino (10), 2-methyl-6-nitro (11), 2,6-dimethyl (12), 2-methyl-3-carboxy (13), 2-methoxycarbonyl (14), 2-methyl-4-methoxy (15), 2,4-dimethoxy (16), 2-chloro-4-amino (17), and 2-chloro-4-nitro (18) N-phenyl substituents of phthalimide were evaluated along with N-[3-methyl-(2-pyridinyl)]phthalimide (19), N-(3-amino-2-methylphenyl)succinimide (20), and phenytoin for anticonvulsant and neurotoxic properties. Initial screening in the intraperitoneal (ip) maximal electroshock-induced seizure (MES) test and the subcutaneous pentylenetetrazol-induced seizure (scPtz) test in mice led to the selection of 1, 2, 4, 10, 12, 17, and 19 for oral MES evaluation in rats. The resultant ED(50) values for 4, 10, 17, and phenytoin were 8.0, 28.3, 5.7 and 29.8 mg/kg, respectively. In the batrachotoxin affinity assay, IC(50) values for 17 and phenytoin were 0.15 and 0.93 microM, respectively, and in the recently validated magnesium deficiency-dependent audiogenic seizure test, ED(50) values of 5.2 and 23 mg/kg were obtained for 17 and phenytoin, respectively. Electrophysiology studies on compound 17 point out its ability to (i) potentiate GABA-evoked current responses with a failure to directly activate the GABAA receptor and (ii) to affect, at 100 microM excitatory non NMDA, but not NMDA, receptors with a 25% block of kainate-evoked response. Electrophysiology measurements on voltage-gated sodium channels in N1E-115 neuroblastoma cells confirm voltage-dependent block of these channels by compound 17. In view of its interaction with multiple ion channels, one would predict that compound 17 might be active in a wide range of seizure models.

Are physiological clonal expansion and maturation pathways a basis for discrepant behaviour of colon tumoral cell growth in response to the thiazolidinedione PPARgamma agonists?

Recently, anti-diabetic thiazolidinediones, pharmacological agonist ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), have been shown to induce either protective or permissive effects towards colon epithelium tumoral cell growth. Several attractive explanations have been proposed but no final answer to these is currently provided. It is not the purpose of the authors to bring this final answer but to offer another attractive hypothesis which might help our approach to explore further this exciting field of medical research.

Medical significance of peroxisome proliferator-activated receptors.

Peroxisome proliferator-activated receptors (PPAR) were discovered in 1990, ending 25 years of uncertainty about the molecular mechanisms of peroxisome proliferation. Subsequently, PPARs have improved our understanding of adipocyte differentiation. But there is more to PPARs than solving a puzzle about an organelle (the peroxisome) long considered an oddity, and their medical significance goes beyond obesity too. Enhanced PPAR type alpha expression protects against cardiovascular disorders though the role of enhanced PPARgamma expression seems less favourable. PPAR mechanisms, mainly via induction of more differentiated cell phenotypes, protect against some cancers. The differentiation of many cell types (hepatocyte, fibroblast, adipocyte, keratinocyte, myocyte, and monocyte/macrophage) involves PPARs, and these nuclear receptors are now attracting the attention of many medical specialties and the pharmaceutical industry.

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 phenytoinergic pharmacophores and anti-HIV activity--preliminary evidence for the dual requirement of the 4-aminophthalimide platform and the N-(1-adamantyl) substitution for antiviral properties.

This work is aimed at further exploring the concept that phenytoin-related compounds might present with an anti-HIV potential. We screened for anti-HIV activity, selected compounds whose structural design rests on pharmacophores successfully shown to convey phenytoinergic anticonvulsant activity. We determined the corresponding anticonvulsant protective doses in mice via the i.p. route of administration using the maximal electroshock seizure test (a test in which the anticonvulsant activity of phenytoin is well expressed). Firstly, 4-aminophthalimide pharmacophores were utilized with either N-(2,6-dimethyl)phenyl or N-(1-adamantyl) substitutions. While the former was found to be highly potent, the latter was devoid of significant activity. Secondly, the pharmacophores N-(2,6-dimethylphenyl)phthalimide and N-(1-adamantyl)phthalimide were compared for antiviral (antiHIV-1 and antiHIV-2) properties in CEM (human T-lymphocyte) cells infected with HIV-1 or HIV-2 strains. Various phthalimide C4-substitutions (H, NO2, NH2, Cl, CH3, OCH3, COOH) of these pharmacophores were studied. From this set of experiments, 4-amino-N-(1-adamantyl)phthalimide emerged with EC50 (effective concentration-50) values of 16 and 27 microM against HIV-1 and HIV-2, respectively. The CC50 (cytostatic concentration-50) of this compound was 30 microM. Thirdly, the N-(2,6-dimethylphenyl) and N-(1-adamantyl) substitutions of the 4-aminobenzamide pharmacophore (another known phenytoinergic anticonvulsant platform) were shown to be devoid of anti-HIV activities. A similar negative result was obtained for amantadine. Taken as a whole, the present data indicate that both the 4-aminophthalimide pharmacophore and N-(1-adamantyl) substitutions are required for anti-HIV properties. Molecular modeling studies further provide clues for this dual requirement.

Anticonvulsant activity and interactions with neuronal voltage-dependent sodium channel of analogues of ameltolide.

Fifteen compounds related to ameltolide (LY 201116) were studied for (i) anticonvulsant potential in the maximal electroshock-induced seizures (MES) and the subcutaneous pentylenetetrazol (sc Ptz) tests in mice and rats and (ii) interactions with neuronal voltage-dependent sodium channels. Compounds were chosen ranging in anticonvulsant activity in mice from very active to inactive. The active compounds were defined as those protecting 50% of the animals at doses between 10 and 50 micromol/kg and inactive compounds as those protecting 50% of the animals at doses greater than 1 mmol/kg. The series studied included three N-(2,6-dimethylphenyl)benzamides (compounds 1, 2 (ameltolide), and 3), three N-(2,2,6, 6-tetramethyl)piperidinyl-4-benzamides (compounds 4, 5, 6), one phenylthiourea (compound 7), five N-(2,6-dimethylphenyl)phthalimides (compounds 8, 9, 10, 13, and 14), two N-phenylphthalimide derivatives (compounds 11 and 12), and one N-(2,2,6, 6-tetramethyl)piperidinyl-4-phthalimide (compound 15). Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. After inital screening in mice, compounds 1, 2, 3, 5, 8, 9, 10, 13, and 14 were selected for further testing in rats. Anticonvulsant ED50s (effective doses in at least 50% of animals tested) of compounds in the MES test were determined in rats dosed orally and amounted to 52 (1), 135 (2), 284 (3), 231 (8), 131 (9), 25 (10), 369 (13), 354 (14), and 121 (PHT) micromol/kg, compound 5 presenting with an ED50 value higher than 650 micromol/kg. In our hands, the apparent IC50s (inhibitory concentrations 50) of compounds toward binding to rat brain synaptosomes of [3H]batrachotoxinin-A-20alpha-benzoate were 0.25 (1), 0.97 (2), 0.35 (3), 25.8 (5), 161.3 (8), 183.5 (9), 0.11 (10), 1.86 (13), 47.8 (14), and 0.86 (PHT) microM. The relationship between the activity in the MES test and the capacity to interact in vitro with neuronal voltage-dependent sodium channels and the fact that the IC50 values obtained in the in vitro test are close to the brain concentrations at which anticonvulsant activities are reported to occur for ameltolide strongly suggest that the anticonvulsant properties of most compounds tested could be a direct result of their interaction with the neuronal voltage-dependent sodium channel.

Metabolic studies in a patient with severe carnitine palmitoyltransferase type II deficiency.

Here we report on a patient with severe ("non-classic") carnitine palmitoyltransferase type II (CPT II) deficiency. Hypoglycemia prompted by an infectious episode and associated with non-ketotic dicarboxylic aciduria orientated diagnosis towards beta-oxidation deficiency disorders. Blood carnitine levels revealed a secondary carnitine deficiency that was responsive to oral L-carnitine supplementation. Blood acylcarnitine profiles were abnormal and included acetyl (C2:0), butyryl/isobutyryl (C4:0), isovaleryl/2-methylbutyryl (C5:0), hexanoyl (C6:0), myristoyl (C14:0), palmitoyl (C16:0), hexadecenoyl (C16:1), oleyl (C18:1) and stearoyl (C18:0) carnitine. In urine, excess excretion of dicarboxylylcarnitines, mainly dodecanedioylcarnitine, was noticed. Upon carnitine supplementation, C8 to C12 fatty acylcarnitines, with decanoylcarnitine as well as C10 to C14 dicarboxylylcarnitines being prominent, were observed in urine. Biochemical measurements disclosed a severe reduction of mitochondrial CPT II activity (7% of normal values). Correlations of metabolic findings in the patient and physiological roles of CPT II are briefly discussed.

Effects of Lorenzo's Oil on peroxisomes in healthy mice.

We investigated peroxisomal alterations in mice treated with different doses of Lorenzo's Oil (a therapy for X-linked adrenoleukodystrophy patients) for up to 100 days. Hepatic erucic acid levels were already significantly increased 2.2-fold and 2.6-fold in mice treated with 10% and 20% Lorenzo's Oil for 21 days, respectively. No lipidosis was found in liver, myocardium and kidney of any of the treated mice. While hepatic catalase, lauroyl-CoA oxidase and glycolate oxidase, and renal catalase activities were not induced by either diet, myocardial catalase activity was increased in most groups. This suggests that the mechanism of the effect of Lorenzo's Oil in X-linked adrenoleukodystrophy patients may not be a direct effect on the peroxisomes.

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties.

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.

Peroxisome-proliferating effects of fenoprofen in mice.

We report on hepatic effects obtained in vivo by treating mice with different doses of fenoprofen, an arylpropionic acid previously shown to inhibit in vitro peroxisomal very long chain fatty acid oxidation. A strong and dose-related induction of peroxisomal palmitoyl-CoA oxidase, and of carnitine acyltransferase and acyl-CoA hydrolase activities was recorded in liver homogenates of mice fed diets supplemented with different contents [0.01, 0.05, 0.1, or 1% (w/w)] of fenoprofen for 6 d. Peroxisomal glycolate oxidase and mitochondrial butyryl-CoA, octanoyl-CoA, and palmitoyl-CoA dehydrogenases were unaffected or increased. Hepatic catalase activity was significantly increased in mice fed the diet with 0.05 and 0.1% fenoprofen but, surprisingly, was not stimulated in mice fed the 1% fenoprofen-containing diet. A time-related but unequal induction of acyl-CoA oxidases and catalase was observed with the 0.1% fenoprofen diet: at 21 d of treatment, the induction of lignoceroyl-CoA and palmitoyl-CoA oxidase activities were five-fold stronger than that of catalase activity. In mice treated with 1% fenoprofen for up to 6 d, only acyl-CoA oxidase activities were found to be significantly increased. Morphometric analysis of the liver peroxisomes in mice treated with 0.1% fenoprofen evidenced an increase in size, volume density, and surface density along with a reduced ratio between perimeter and area of the peroxisomal profiles. No morphological marker for very long chain fatty acid deposition could be detected in livers from fenoprofen-treated animals. Our findings clearly demonstrate that fenoprofen acts as a peroxisome proliferator in the liver of mice and do not support the occurrence of in vivo reduction of very long chain fatty acid oxidation in liver from treated animals.

Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism.

Peroxisome proliferation (PP) in mammalian cells, first described 30 years ago, represents a fascinating field of modern research. Major improvements made in its understanding were obtained through basic advances that have opened up new areas in cell biology, biochemistry and genetics. A decade after the first report on PP, a new metabolic pathway (peroxisomal beta-oxidation) and its inducibility by peroxisome proliferators were discovered. More recently, a new type of nuclear receptor, the peroxisome proliferator-activated receptor (PPAR), has been described. The first PPAR was discovered in 1990. Since then, many other PPARs have been characterized. This original class of nuclear receptors belongs to the superfamily of steroid receptors. With activation of cell signal transduction pathways, the occurrence of PPARs provides, for the first time, a coherent explanation of mechanisms by which PP is triggered. Nevertheless, although many compounds or metabolites are capable of activating PPARs, the natural direct ligands of these receptors have not been, up to now, clearly identified, with, however, the exception of 15-deoxy-12,14-prostaglandin J2 which is the ligand of PPAR gamma 2 while leukotrien LTB4 binds PPAR alpha. At this stage, the hypothesis of some orphan PPARs (ie receptors without known ligand) can not be ruled out. Despite these relatively restrictive aspects, the mechanisms by which activation of PPARs leads to PP become clear; also, coherent hypotheses among which a scenario involving receptor phosphorylation or a heat shock protein (ie HSP 72) can be proposed to explain how PPARs would be activated. The aim of this note is to review recent developments on PPARs, to present members up to now recognized to belong to the PPAR family, their characterization, functions, regulation and mechanisms of activation as well as their involvement in lipid metabolism regulation such as control of beta-oxidation, ketogenesis, fatty acid synthesis and lipoprotein metabolism. As an introducing section, a brief review of the major events between the first report of PP in mammals and the discovery of the first PPAR is given. Another section is devoted to current hypotheses on mechanisms responsible for PPAR activation and PP induction. Rather than an exhaustive presentation of cellular alterations accompanying PP induction, a dynamic overview of the lipid metabolism is provided. By assessing the biological significance of this organellar proliferative process, the reader will be led to conclude that the discovery of PPARs and related gene activation through peroxisome proliferator responsive element (PPRE) makes PP induction one of the most illustrative examples of control that occurs in lipid metabolism.

Effect of vitamin E on antioxidant enzymes, lipid peroxidation products and glomerulosclerosis in the rat remnant kidney.

In rats with five-sixth nephrectomy (remnant kidney), glomerulosclerosis was significantly reduced by dietary administration of vitamin E (alpha-tocopherol) during 11 and 16 weeks after reduction of nephron number. The activity of catalase and the production of H2O2 in remnant kidney cortex homogenate were not influenced by the vitamin E diet; however, the activities of glutathione peroxidase and superoxide dismutase were significantly increased (up to 140 and 180%, respectively, after 16 weeks). Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentrations, was decreased in cortex homogenates and in urine. Though the extent of the effect of vitamin E on antioxidant enzyme levels and lipid peroxidation is small, the important reduction of glomerulosclerosis is in favor of dietary supplementation with vitamin E.

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.