Abstract

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.