NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.
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.
Mueller
A L
AL
NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108, USA. amueller@npsp.com
Artman
L D
LD
Balandrin
M F
MF
Brady
E
E
Chien
Y
Y
Delmar
E G
EG
George
K
K
Kierstead
A
A
Marriott
T B
TB
Moe
S T
ST
Newman
M K
MK
Raszkiewicz
J L
JL
Sanguinetti
E L
EL
van Wagenen
B C
BC
Wells
D
D
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
D005464:Fluorobenzenes; D018696:Neuroprotective Agents; D011437:Propylamines; D016194:Receptors, N-Methyl-D-Aspartate; C016411:3,3-diphenylpropylamine; C405105:NPS 1506