Klaus Unverferth

AWD 140-190: a new anticonvulsant with a very good margin of safety

The anticonvulsant activity of the novel drug AWD 140-190 (4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) was evaluated in animal models of epileptic seizures. AWD 140-190 was active at nontoxic doses after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests. The compound was active against electrically-induced seizures (MES, ED50 rat p.o. = 2.47 mg/kg), in a genetic animal model the DBA/2 mouse, and in corneally kindled rats. It was not active against seizures induced chemically by pentylenetetrazole, bicuculline and strychnine. Effective doses in mice following both oral and intraperitoneal administration are similar indicating good oral absorption. During 14 days chronic oral treatment of mice with 10 mg/kg, no development of tolerance was observed. The protective indices (TD50/MES ED50) in rats and mice following oral administration are favorable when compared to phenytoin, carbamazepine and valproate. No motor impairment, evaluated with the rotarod test and by observation in the open field test, was observable following oral administration of doses up to 500 mg/kg. There was no influence on spontaneous motility and learning performance in rats and no interaction with ethanol in mice after administration of doses which are above anticonvulsant effective doses indicating the absence of central side effects. AWD 140-190 thus presents an orally active and safe anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used.

3-Amino- and 5-aminopyrazoles with anticonvulsant activity

New 3‐amino‐ and 5‐aminopyrazoles were synthesised. 3‐Aminopyrazoles exert a strong anticonvulsant effect. 4‐Chlorophenyl‐3‐( morpholin‐4‐yl)‐1H‐pyrazole 2 distinctively blocks sodium channels and is strongly effective in the Maximal Electroshock Seizure (MES) test.

Theoretical description of the conformation and the tautomerism of progabide

Abstract A theoretical description of the conformation and tautomerism of the progabide molecule was performed employing the ab initio STO-3G and 3-21G basis sets and a quantum chemical reaction field model for the consideration of the solvent influence. The calculations indicated a conformation with planar orientation of the A ring and considerable rotation of the B ring with respect to the imine bond as the most stable conformation. The consequences for conformation of hydrogen bond formation and breaking were examined. Predominance of the aromatic tautomer in apolar and the quinonoid tautomer in polar solvents is predicted.A theoretical description of the conformation and tautomerism of the progabide molecule was performed employing the ab initio STO-3G and 3-21G basis sets and a quantum chemical reaction field model for the consideration of the solvent influence. The calculations indicated a conformation with planar orientation of the A ring and considerable rotation of the B ring with respect to the imine bond as the most stable conformation. The consequences for conformation of hydrogen bond formation and breaking were examined. Predominance of the aromatic tautomer in apolar and the quinonoid tautomer in polar solvents is predicted.