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A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.

The marketed antiepileptic drugs can not solve entirely the problem of seizure in patients suffering from refractory epilepsies. Therefore, new anticonvulsant compounds structurally and pharmacologically different of the currently prescribed drugs are needed. Carbonic anhydrase (CA) inhibitors are known to act as anticonvulsant since several decades while the link between CA and seizure is not straightforward. However, the recent discovery that several CA isozymes are expressed in brain and the better knowledge of their physiological/pathological role, lead to the emergence of new CA inhibitors with anticonvulsant effect including: analogues of acetazolamide, analogues of topiramate, aromatic or heterocyclic sulfonamides incorporating valproyl or adamantyl moieties. Different strategies are developed for the design of new more selective CA inhibitors with anticonvulsant properties.

Seizures are one of the most common neurological disorders in clinical medicine. Triggering mechanisms by which seizures form remain unclear, but are related to a rapid change in ionic composition, including an increase of intracellular potassium concentration and pH shifts within the brain. pH buffering of extra- and intracellular spaces is mainly carried out by the CO(2)/ HCO(3)(-) buffer, the equilibration of the two species being assured by the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Some carbonic anhydrase inhibitors (CAIs) are used as anticonvulsants in the treatment of epilepsy. In this review, we will describe the link between CA and seizures on the basis of several putative mechanisms. Several CA isozymes have been pointed out for their contribution to epileptiform activity. An overview of the CA isozyme expression in the brain and of their specifics roles is also discussed. This article reviews the research achievements published on CA inhibitors, clinically used as anticonvulsant and those under development.

A series of aromatic sulfonamides incorporating indane moieties were prepared starting from commercially available 1- and 2-indanamine, and their activity as inhibitors of two carbonic anhydrase (CA, EC 4.2.1.1) isozymes, hCA I and II was studied. The new sulfonamides incorporating acetamido, 4-chloro-benzoyl, valproyl, tetra-, and pentafluorobenzoyl moieties acted as very potent inhibitors of the slow red blood cell isozyme hCA I (K(i)s in the range of 1.6-8.5 nM), which usually has a lower affinity for such inhibitors, as compared to isozyme II. Some derivatives also showed excellent hCA II inhibitory properties (K(i)s in the range of 2.3-12 nM), but the anticonvulsant activity of these sulfonamides was rather low as compared to that of other sulfonamide/sulfamate CA inhibitors, such as methazolamide. Furthermore, the 2-amino/acetamido-indane-5-sulfonic acids prepared during this work also showed interesting CA inhibitory properties, with inhibition constants in the range of 43-89 nM against the two isozymes, being among the most potent sulfonic acid CA inhibitors reported so far.

A series of aromatic/heterocyclic sulfonamides incorporating adamantyl moieties were prepared by reaction of aromatic/heterocyclic aminosulfonamides with the acyl chlorides derived from adamantyl-1-carboxylic acid and 1-adamantyl-acetic acid. Related derivatives were obtained from the above-mentioned aminosulfonamides with adamantyl isocyanate and adamantyl isothiocyanate, respectively. Some of these derivatives showed good inhibitory potency against two human CA isozymes involved in important physiological processes, CA I, and CA II, of the same order of magnitude as the clinically used drugs acetazolamide and methazolamide. The lipophilicity of the best CA inhibitors was determined and expressed as their experimental log k' IAM and theoretical ClogP value. Their lipophilicity was propitious with the crossing of the blood-brain barrier (log k' > IAM > 1.35). The anticonvulsant activity of some of the best CA inhibitors reported here has been evaluated in a MES test in mice. After intraperitoneal injection (30 mg kg(-1)), compounds A8 and A9 exhibited a high protection against electrically induced convulsions (> 90%). Their ED50 was 3.5 and 2.6 mg kg(-1), respectively.

A series of aromatic/heterocyclic sulfonamides incorporating valproyl moieties were prepared to design antiepileptic compounds possessing in their structure two moieties known to induce such a pharmacological activity: valproic acid, one of the most widely used antiepileptic drugs, and the sulfonamide residue included in acetazolamide and topiramate, two carbonic anhydrase inhibitors with antiepileptic properties. Some of these derivatives showed very high inhibitory potency against three carbonic anhydrase (CA) isozymes, such as CA I, CA II, and CA IV, involved in important physiological processes. Topiramate, a recently developed antiepileptic drug possessing a sulfamate moiety, also shares this property, although earlier literature data reported this compound to be a weak-moderate CA I, II, and IV inhibitor. The valproyl derivative of acetazolamide (5-valproylamido-1,3,4-thiadiazole-2-sulfonamide, 6M) was one of the best hCA I and hCA II inhibitor in the series and exhibited very strong anticonvulsant properties in an MES test in mice. In consequence, other 1,3,4-thiadiazolesulfonamide derivatives possessing potent CA inhibitory properties and substituted with different alkyl/arylcarboxamido/sulfonamido/ureido moieties in the 5 position have been investigated for their anticonvulsant effects in the same animal model. It was observed that some lipophilic derivatives, such as 5-benzoylamido-, 5-toluenesulfonylamido-, 5-adamantylcarboxamido-, and 5-pivaloylamido-1,3,4-thiadiazole-2-sulfonamide, show promising in vivo anticonvulsant properties and that these compounds may be considered as interesting leads for developing anticonvulsant or selective cerebrovasodilator drugs.

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.

The lipophilic 1-cycloalkylamino-1-(pyrid-3-yl-sulfonamido)-2-nitr oethylenes were synthesized as bioisosteres of BM-34, an anticonvulsant sulfonylthiourea. Compound 17 (ip) emerged from the maximal electroshock seizure (MES) test with a 50% effective dose (ED50) of 8.25 mg/kg. Its anticonvulsant profile was similar to that of phenytoin (ED50 = 9.51 mg/kg) and of BM-34 (ED50 = 1.19 mg/kg): active in the MES test and inactive in seizures induced by subcutaneous injection of pentetrazole, strychnine, bicuculline, picrotoxin, or N-methyl-D,L-aspartate. The neurotoxicity of 17 (TD50 = 113.8 mg/kg) was lower than that of phenytoin (TD50 = 65.5 mg/kg) but higher than that of BM-34 (TD50 = 147.2 mg/kg). Crystallographic study revealed that BM-401 (17) was a zwitterionic structure. Its sulfonamido nitroethylene side chain adopted a conformation which placed the two cycloalkyl rings face to face to form a single hydrophobic area.

A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar affinities.

Pharmacomodulation of torasemide, a diuretic sulfonylurea, led to the discovery of two novel diuretics, a sulfonylthiourea (BM 20) and a sulfonylcyanoguanidine (BM 106). BM 27, a lipophilic sulfonylurea, exhibited neuroprotective properties associated to an anticonvulsant activity. As BM 27, two lipophilic sulfonythioureas (BM 11 and BM 34) revealed an anticonvulsant profile similar to that of phenytoin. Finally the synthesis of torasemide derivatives led to the development of a sulfonylcyanoguanidine (BM 144) with a thromboxane A2 antagonist potency.

The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two structurally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED50) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest.

Phenytoin is extensively used in Europe and the United States for the treatment of generalized tonic clonic seizures (grand mal). However, the efficacy is lowered by the erratic bioavailability after oral administration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsant activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogue of phenytoin, which was obtained by the replacement of the urea moiety by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneous Biltz conditions and under heterogeneous phase-transfer conditions. CNG-DPH is poorly water soluble and has a pKa of 5.3. At pH 7.4, log P was 1.16, from which a pH-independent log P of 3 can be calculated. Pharmacokinetic parameters were obtained after oral administration of CNG-DPH to rats and were compared to those of phenytoin after administration of an equimolar amount. AUC, tmax, and Cmax were significantly increased compared to those of phenytoin. The anticonvulsant profile was similar to the profile of phenytoin. CNG-DPH was active in the maximal electroshock seizure test, albeit 7-fold less active than phenytoin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methyl-aspartate, strychnine, and bicuculline. It is concluded that while the bioisosteric exchange of the urea moiety of the molecule with the cyanoguanidine moiety dramatically changed the physicochemical and pharmacokinetic parameters compared to those of phenytoin, the concomitant change of the affinity toward molecular targets reduced the pharmacological activity and the therapeutic efficacy of the compound.