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

A rational, chemical, synthetic effort to identify promising low-affinity u ncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antie pileptic 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. AR-R 15896AR preven ted tonic seizures in rodents for up to 6 to 8 h in response to maximal ele ctroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as ch aracteristic seizures following injections of N-methyl-DL-aspartic or kaini c acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, d id not produce tolerance to MES, and was devoid of proconvulsant and phency clidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticon vulsants. Orally administered AR-R 15896AR rapidly entered the rat brain an d 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 co rrelative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentr ation (25 mu M) of drug at the ED50 Value (similar to 3 mg/kg) for protecti on against MES seizures was consistent with the reported affinity of AR-R 1 5896AR at the N-methyl-D-aspartic acid binding site (IC50 value = 1.3 mu M) . The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy.