[S]-AR-R 15896AR-A novel anticonvulsant: acute safety, pharmacokinetic and pharmacodynamic properties.

A rational, chemical, synthetic effort to identify promising low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-alpha-phenyl-2-pyridine-ethanamine.2HCl. Chiral separation followed by intensive in vivo screening resulted in the selection of the [S] enantiomer, AR-R 15896AR, as the best compound for further preclinical development.

-(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia.

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons.

Neuroprotective actions of 2-amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) in animal models of hypoxia and global ischemia.

2-Amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) has been demonstrated to have good anticonvulsant efficacy and a relative lack of acute side effects in rodents. Similar in structure to remacemide hydrochloride, it was also shown to possess weak potency as an uncompetitive antagonist of N-methyl-D-aspartic acid (NMDA) receptors. In our study FPL 13950 was profiled preclinically as a potential neuroprotective agent with respect to lengthening the survival time of rodents exposed to hypoxia, as well as for ability to protect the vulnerable CA1 pyramidal neurons of the rat and dog from the consequences of global ischemia.

Anticonvulsant efficacy/safety properties of 2-amino-N-(1,2-diphenylethyl)acetamide hydrochloride.

2-Amino-N-(1,2-diphenylethyl)-acetamide-hydrochloride (FPL 13950) was profiled preclinically in rodents for efficacy against convulsions, as well as for acute safety/behavioral observations. FPL 13950 exhibited good oral efficacy and duration of action with respect to prevention of seizures elicited by maximal electroshock-shock in both rats and mice. Tolerance to protection against maximal electroshock and hexobarbital-induced sleep-time was not evident after subchronic drug administration.

Kainic acid and 4-aminopyridine seizure models in mice: evaluation of efficacy of anti-epileptic agents and calcium antagonists.

Seizures may be induced in mice in response to stimulation of subtypes of glutamate receptors by kainic acid or inhibition of certain voltage-dependent potassium channels by 4-aminopyridine (4-AP). The anti-seizure efficacy of intraperitoneally administered anticonvulsants and Ca++ antagonists to CF-1 mice was tested using these models. The order of potency for prevention of kainate convulsions and the subsequent lethality was: dihydropyridine Ca++ antagonists (nicardipine, nisoldipine > nitrendipine > nifedipine > nimodipine) followed by verapamil > prenylamine > diltiazem > flunarizine > remacemide HCl > ethosuximide > valproate.