title: ARL-15896, a novel N-methyl-D-aspartate receptor ion channel antagonist: neuroprotection against mitochondrial metabolic toxicity and regional pharmacology.
abstract: ARL-15896 [(+)-alpha-phenyl-2-pyridineethanamine], formerly known as FPL-15896, is a novel N-methyl-D-aspartate (NMDA) receptor ion channel antagonist. Using quantitative receptor autoradiography, we examined the regional binding characteristics of ARL-15896 and compared them to those of MK-801, the prototypical NMDA receptor channel blocker. The affinity 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 than in the forebrain (IC50 of 17 microM vs 45 microM). The neuroprotective potential of ARL-15896 was investigated in a rat model of excitotoxicity, 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-15896 either intrastriatally (200 nmol) or subcutaneously (9.0 mg/kg) reduced the volume of the lesion produced by 1 mumol of malonate by 80%, a degree similar to that reported for MK-801. ARL-15896 was also protective when administered after the malonate injection. Furthermore, in contrast to MK-801, administration of ARL-15896 was not associated with any apparent behavioral side effects. This report is consistent with previous studies suggesting that drugs with regional pharmacological profiles similar to that of ARL-15896 have better clinical tolerability; it also indicates that ARL-15896 is an effective neuroprotective agent.
authors.affiliation: Department of Neurobiology & Anatomy, University of Rochester Medical Center, New York 14642, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Greene
authors.forename: R H
authors.initials: RH
authors.lastname: Porter
authors.forename: J T
authors.initials: JT
authors.lastname: Greenamyre
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008314:Malonates / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D008314:Malonates; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate