ly-233053 and Seizures

The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 l(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-qu inoline-3-carboxylic acid; < or = 0.5 mg/kg] or LY 233053 cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl]piperidine-2-carboxylic acid; < or = 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice.. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, reiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance ask (long-term memory). Plasma levels of antiepileptic rugs were measured by immunofluorescence.. Both LY 235959 and LY 233053 ( < or = 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied.. It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.

Topics: Animals; Anticonvulsants; Avoidance Learning; Disease Models, Animal; Drug Synergism; Electroshock; Epilepsy; Excitatory Amino Acid Antagonists; Female; Humans; Isoquinolines; Kindling, Neurologic; Memory; Mice; Motor Activity; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Seizures; Tetrazoles

The tetrazole-substituted amino acid (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)pip eri dine-2-carboxylic acid (LY233053, (+/-)-1) was resolved into its constituent enantiomers by treatment of a key intermediate in the synthesis of the racemic amino acid, ethyl (+/-)-cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate, with either 2S,3S- or 2R,3R-di-p-toluoyltartaric acid. These resolved amines were then converted as for the racemate to the amino acids (-)-1 and (+)-1. The activity of this potent and selective NMDA antagonist was found to reside with the (-)-isomer of 1 (LY235723). X-ray crystallographic analysis of the 2S,3S-di-p-toluoyltartaric acid salt of ethyl cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate showed that the resolved amine, and thus (-)-1, possessed the 2R,4S absolute stereochemistry. Affinity for the NMDA receptor was determined using the specific radioligand [3H]-(2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid ([3H]CGS 19755; IC50 = 67 +/- 6 nM), and selective NMDA antagonist activity was determined using a cortical slice preparation (IC50 versus 40 microM NMDA = 1.9 +/- 0.24 microM). This compound also demonstrated potent NMDA antagonist activity in vivo following systemic administration through its ability to block NMDA-induced convulsions in neonatal rats, NMDA-induced lethality in mice, and NMDA-induced striatal neuronal degeneration in rats.

Topics: Animals; Animals, Newborn; Corpus Striatum; Mice; Molecular Structure; N-Methylaspartate; Nerve Degeneration; Pipecolic Acids; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Structure-Activity Relationship; Tetrazoles; X-Ray Diffraction

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity. The relatively short duration of action of LY233053 may make this compound particularly advantageous as a neuroprotective agent in the treatment of acute conditions such as cerebral ischemia.

Topics: Administration, Oral; Animals; Animals, Newborn; Behavior, Animal; Binding, Competitive; Dose-Response Relationship, Drug; Electroshock; Female; Injections, Intraperitoneal; Male; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures; Tetrazoles; Tritium

Topics: Animals; Binding, Competitive; Brain; Dose-Response Relationship, Drug; Kinetics; Mice; N-Methylaspartate; Neurons; Pipecolic Acids; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Tetrazoles