Bioavailability and Anticonvulsant Activity of 2-Cyanoguanidinophenytoin, a Structural Analogue of Phenytoin

Abstract

0 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 pK a 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, t max , and C max 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-methylaspartate, 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.

Voltage-gated Na+ channel ligands and ATP: relative molecular similarity and implications for channel function

“…In this study, the anticonvulsant fitting motif is based on an alternative group of adjacent atoms within the hydantoin moiety of phenytoin (positions 2, 3, 4) and ATP, with commonality to other anticonvulsant structures. The pharmacological potency of phenytoin is reduced by alteration of the hydantoin moiety through methylation, cyanoguanidino substitution at position 2 and conversion into succinimide or pyrrolidine rings (Poupaert et al 1984;Lambert et al 1996), whereas a tertiary amine chain at position 3 changes the drug profile to a quinidine-like preference for activated channels (Ciechanowicz-Rutowska et al 2000).…”

Synthesis and evaluation of phenytoin derivatives as anticonvulsant agents

“…The log P of the synthesized compounds was determined to see the effect of the attached moiety on The log P values of the target compounds were calculated by the following method, 9 10 mL of octanol and 10 mL of phosphate buffer (pH 7.4) were taken in a separating funnel. Then 10 mg of compound 4a-c, 5a-b was added to the mixture, which was shaken for 3 h and then kept undisturbed overnight.…”

Study of Some Hyndantion Derivatives as Anticonvulsant Agents

“…The analogue did not protect animals against convulsions induced by chemicals such as PTZ, picrotoxin, N-methyl-aspartate, strychnine, and bicuculline. 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 [17]. The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3dimyristoylglyceryl)butyric acid and to 3myristoyl-2-myristoylmethylpropionic acid was evaluated in the MES test and scPTZ.…”