strychnine and Ataxia

A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-D-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on alpha-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5, 7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of these compounds on VSNaCs and NMDA receptors also impart properties to these compounds that are important for preventing and reducing excitotoxic neurodegeneration, but these compounds lack the undesirable side effects of other agents used for these purposes.

Topics: Animals; Anti-Anxiety Agents; Ataxia; Behavior, Animal; Binding Sites; Binding, Competitive; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; Ethanol; Glycine; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neurons; Oocytes; Phenylurea Compounds; Protein Binding; Quinolines; Rats; Receptors, Adrenergic, alpha; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channel Blockers; Sodium Channels; Sound; Strychnine; Substance Withdrawal Syndrome; Xenopus

Two experiments examined the involvement of the strychnine-insensitive glycine binding site (SIGBS) of the N-methyl-D-aspartate (NMDA) receptor/channel complex in feeding behavior. The first experiment demonstrated that the SIGBS antagonist, 7-chlorokynurenic acid (7CK), dose-dependently increased food intake in rats without producing significant locomotor deficits or stereotypies. The second experiment showed that D-serine, a SIGBS agonist, dose-dependently antagonized 7CK induced feeding, such that at the highest dose of D-serine used 7CK induced feeding was completely abolished, demonstrating that the effects of 7CK are specific to an action at the SIGBS.

Topics: Analysis of Variance; Animals; Ataxia; Dose-Response Relationship, Drug; Feeding Behavior; Glycine; Injections, Intraventricular; Kynurenic Acid; Male; Muscle Contraction; Rats; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Serine; Strychnine

Topics: Animals; Anticonvulsants; Antihypertensive Agents; Ataxia; Barbiturates; Behavior, Animal; Blood Pressure; Body Temperature; Cholinesterase Inhibitors; Drug Synergism; Electroshock; Hydroxylamines; Mice; Pentylenetetrazole; Sleep; Strychnine

Topics: Acetates; Animals; Ataxia; Behavior; Caffeine; Catalepsy; Central Nervous System; Drug Interactions; Drug Synergism; Electroencephalography; Humans; Hydroxybutyrates; Imidazoles; Injections, Intraperitoneal; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentylenetetrazole; Phenobarbital; Picrotoxin; Rats; Rats, Inbred Strains; Sleep; Stimulation, Chemical; Strychnine; Time Factors

Topics: Anesthetics; Animals; Antidotes; Ataxia; Electromyography; Isonicotinic Acids; Male; Mephenesin; Mice; Muscle Relaxants, Central; Paralysis; Phenobarbital; Rabbits; Seizures; Strychnine; Tetanus; Tetanus Toxin