title: NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.
abstract: NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.
authors.affiliation: NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108, USA. amueller@npsp.com
authors.forename: A L
authors.initials: AL
authors.lastname: Mueller
authors.forename: L D
authors.initials: LD
authors.lastname: Artman
authors.forename: M F
authors.initials: MF
authors.lastname: Balandrin
authors.forename: E
authors.initials: E
authors.lastname: Brady
authors.forename: Y
authors.initials: Y
authors.lastname: Chien
authors.forename: E G
authors.initials: EG
authors.lastname: Delmar
authors.forename: K
authors.initials: K
authors.lastname: George
authors.forename: A
authors.initials: A
authors.lastname: Kierstead
authors.forename: T B
authors.initials: TB
authors.lastname: Marriott
authors.forename: S T
authors.initials: ST
authors.lastname: Moe
authors.forename: M K
authors.initials: MK
authors.lastname: Newman
authors.forename: J L
authors.initials: JL
authors.lastname: Raszkiewicz
authors.forename: E L
authors.initials: EL
authors.lastname: Sanguinetti
authors.forename: B C
authors.initials: BC
authors.lastname: van Wagenen
authors.forename: D
authors.initials: D
authors.lastname: Wells
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005464:Fluorobenzenes / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011437:Propylamines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000188:drug therapy
chemical_list: D005464:Fluorobenzenes; D018696:Neuroprotective Agents; D011437:Propylamines; D016194:Receptors, N-Methyl-D-Aspartate; C016411:3,3-diphenylpropylamine; C405105:NPS 1506