RT Journal Article SR Electronic T1 [S]-AR-R 15896AR—A Novel Anticonvulsant: Acute Safety, Pharmacokinetic and Pharmacodynamic Properties JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 121 OP 132 VO 288 IS 1 A1 Gene C. Palmer A1 Robert J. Murray A1 Carrie L. Cramer A1 Mary L. Stagnitto A1 Marilyn K. Knowles A1 Lou R. Freedman A1 Mark S. Eismann A1 Nik Mahmood A1 Mike Balestra A1 Alfonso R. Borrelli A1 Thomas J. Hudzik A1 Dennis J. McCarthy YR 1999 UL http://jpet.aspetjournals.org/content/288/1/121.abstract AB A rational, chemical, synthetic effort to identify promising low-affinity uncompetitiveN-methyl-d-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-α-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. AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections ofN-methyl-dl-aspartic or kainic acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, did not produce tolerance to MES, and was devoid of proconvulsant and phencyclidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticonvulsants. Orally administered AR-R 15896AR rapidly entered the rat brain and was eliminated in parallel from the plasma and plasma-free compartment. A dose-response relationship between plasma and brain levels after p.o. or i.v. administration of AR-R 15896AR and protection against MES was highly correlative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentration (25 μM) of drug at the ED50 value (∼3 mg/kg) for protection against MES seizures was consistent with the reported affinity of AR-R 15896AR at theN-methyl-d- aspartic acid binding site (IC50 value = 1.3 μM). The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy. The American Society for Pharmacology and Experimental Therapeutics