title: Anticonvulsant activity of novel derivatives of 2- and 3-piperidinecarboxylic acid in mice and rats.
abstract: The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) 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 elevation of threshold for electroshock-induced seizures and rotorod performance ranged from > 1.6 to > 20 for both types of derivatives. Since preliminary data indicated that benzylamide derivatives of 2-PC displace [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine (TCP) binding to the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor in the micromolar range and such low affinity uncompetitive antagonists of the NMDA receptor-associated ionophore have been shown to be effective anticonvulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP site. Although all compounds inhibited [3H]TCP binding, a clear correlation between pharmacological activity and binding affinity was not apparent. Select compounds demonstrated minimal ability to protect against pentylenetetrazol-, 4-aminopyridine- and NMDA-induced seizures in mice. Corneal and amygdala kindled rats exhibited different sensitivities to both valproic acid and the nonsubstituted 2-PC benzylamide, suggesting a difference in these two models. Enantiomers of the alpha-methyl substituted benzylamide of 2-PC showed some ability to reduce seizure severity in amygdala kindled rats.
authors.affiliation: College of Pharmacy, University of Toledo, OH 43606, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Hinko
authors.forename: A M
authors.initials: AM
authors.lastname: Crider
authors.forename: M A
authors.initials: MA
authors.lastname: Kliem
authors.forename: C L
authors.initials: CL
authors.lastname: Steinmiller
authors.forename: T H
authors.initials: TH
authors.lastname: Seo
authors.forename: B
authors.initials: B
authors.lastname: Ho
authors.forename: P
authors.initials: P
authors.lastname: Venkatarangan
authors.forename: A A
authors.initials: AA
authors.lastname: el-Assadi
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.forename: C M
authors.initials: CM
authors.lastname: Burns
authors.forename: E I
authors.initials: EI
authors.lastname: Tietz
authors.forename: P H
authors.initials: PH
authors.lastname: Andersen
authors.forename: H
authors.initials: H
authors.lastname: Klitgaard
mesh_terms: D015761:4-Aminopyridine; D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D003292:Convulsants; D007696:Kindling, Neurologic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D016202:N-Methylaspartate; D009498:Neurotoxins / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology*; D010433:Pentylenetetrazole; D010875:Pipecolic Acids / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017478:Receptors, Phencyclidine / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D009498:Neurotoxins; D009557:Nipecotic Acids; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; C030278:nipecotic acid; D014635:Valproic Acid; D016202:N-Methylaspartate; D011392:Proline; D015761:4-Aminopyridine; C010983:homoproline; C031345:pipecolic acid; D010433:Pentylenetetrazole