ANTICONVULSANT ACTIVITY OF NOVEL DERIVATIVES OF 2-PIPERIDINECARBOXYLIC AND 3-PIPERIDINECARBOXYLIC ACID IN MICE AND RATS

The relative ability of derivatives of 2-piperidinecarboxylic acid (2- PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic a cid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated. Protective index (PI) values, based on the MES test and rotorod performance, ranged from 1.3 to 4.5 for 2-PC benzylamides and from <1 to >7.2 for 3-PC derivatives. PI values based on elevatio n of threshold for electroshock-induced seizures and rotorod performan ce ranged from >1.6 to >20 for both types of derivatives. Since prelim inary data indicated that benzylamide derivatives of 2-PC displace [H- 3]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) binding to the phencycli dine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor in the mic romolar range and such low affinity uncompetitive antagonists of the N MDA receptor-associated ionophore have been shown to be effective anti convulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP sit e. Although all compounds inhibited [H-3]TCP binding, a clear correlat ion between pharmacological activity and binding affinity was not appa rent. Select compounds demonstrated minimal ability to protect against pentylene-tetrazol-, 4-aminopyridine- and NMDA-induced seizures in mi ce. Corneal and amygdala kindled rats exhibited different sensitivitie s to both valproic acid and the nonsubstituted 2-PC benzylamide, sugge sting a difference in these two models. Enantiomers of the alpha-methy l substituted benzylamide of 2-PC showed some ability to reduce seizur e severity in amygdala kindled rats. (C) 1997 Elsevier Science Ltd.