ly-233053 and selfotel

N-methyl-D-aspartate antagonists are effective in limiting ischemic damage to the brain and spinal cord if treatment is begun at time of ischemic injury. More clinically relevant delayed therapy has not been adequately investigated. We report the temporal profile of efficacy for two competitive N-methyl-D-aspartate antagonists in therapy of central nervous system ischemia.. CGS-19755 (30 mg/kg) or LY233053 (100 mg/kg) was administered 5, 30, or 60 minutes after reversible spinal cord ischemia in rabbits, induced by temporary occlusion of the infrarenal aorta. Duration of occlusion for individual animals was varied to provide a range of ischemia for each experimental group. The P50 represents the duration (in minutes) associated with a 50% probability of resultant permanent paraplegia. Neuroprotection is demonstrated if a drug prolongs the P50.. CGS-19755 significantly prolonged the P50 (t test, P = .003) when given 5 minutes after ischemia, but not if delayed by 30 or 60 minutes (P50: control, 24.1; 5 minutes, 31.4; 30 minutes, 30.1; 60 minutes, 26.6). LY233053 was efficacious at 5 (P = .0008) and 30 (P = .002) minutes, but not at 60 minutes (P50: control, 26.8; 5 minutes, 39.4; 30 minutes, 36.0; 60 minutes, 25.6).. These competitive N-methyl-D-aspartate antagonists are effective in limiting ischemic damage, but protection is lost if therapy is not initiated within 60 minutes of injury.

Topics: Animals; Ischemia; N-Methylaspartate; Paraplegia; Pipecolic Acids; Rabbits; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Tetrazoles; Time Factors

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