ARL-15896, A NOVEL N-METHYL-D-ASPARTATE RECEPTOR-ION CHANNEL ANTAGONIST - NEUROPROTECTION AGAINST MITOCHONDRIAL METABOLIC TOXICITY AND REGIONAL PHARMACOLOGY

ARL-15896 [(+)-alpha-phenyl-2-pyridineethanamine], formerly known as F PL-15896, is a novel N-methyl-D-aspartate (NMDA) receptor ion channel antagonist. Using quantitative receptor autoradiography we examined th e regional binding characteristics of ARL-15896 and compared them to t hose of MK-801, the prototypical NMDA receptor channel blocker. The af finity of ARL-15896 was much lower (3000-fold) than that of MK-801 in all brain regions examined. In addition, in contrast to MK-801, which has a higher affinity in the forebrain than in the cerebellum (IC50 of 10 nM vs 24 nM), ARL-15896 had a higher affinity in the cerebellum th an in the forebrain (IC50 of 17 mu M vs 45 mu M). The neuroprotective potential of ARL-15896 was investigated in a rat model of excitotoxici ty, the intrastriatal injection of malonate. Malonate is a competitive inhibitor of succinate dehydrogenase, and its toxicity has been shown to be mediated largely by the NMDA receptor. Administration of ARL-15 896 either intrastriatally (200 nmol) or subcutaneously (9.0 mg/kg) re duced the volume of the lesion produced by 1 mu mol of malonate by 80% , a degree similar to that reported for MK-801. ARL-15896 was also pro tective when administered after the malonate injection. Furthermore, i n contrast to MK-801, administration of ARL-15896 was not associated w ith any apparent behavioral side effects. This report is consistent wi th previous studies suggesting that drugs with regional pharmacologica l profiles similar to that of ARL-15896 have better clinical tolerabil ity; it also indicates that ARL-15896 is an effective neuroprotective agent. (C) 1996 Academic Press, Inc.