Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease

Carol Addy, Chris Assaid, David Hreniuk, Mark Stroh, Yang Xu, W. Joseph Herring, Aaron Ellenbogen, H. A. Jinnah, Louis Kirby, Mark T. Leibowitz, R. Malcolm Stewart, Daniel Tarsy, James Tetrud, S. Aubrey Stoch, Keith Gottesdiener, John Wagner

Research output: Contribution to journalArticle

Abstract

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selctive NMDA receptor antagonist. Patients (n = 16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P =.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P =.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)856-864
Number of pages9
JournalJournal of Clinical Pharmacology
Volume49
Issue number7
DOIs
StatePublished - Jul 2009
Externally publishedYes

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N-Methylaspartate
Parkinson Disease
Placebos
Blood Pressure
4-methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate
Cross-Over Studies

Keywords

  • Glutamate receptor
  • NMDA
  • NR2B
  • Parkinson's disease

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease. / Addy, Carol; Assaid, Chris; Hreniuk, David; Stroh, Mark; Xu, Yang; Herring, W. Joseph; Ellenbogen, Aaron; Jinnah, H. A.; Kirby, Louis; Leibowitz, Mark T.; Stewart, R. Malcolm; Tarsy, Daniel; Tetrud, James; Stoch, S. Aubrey; Gottesdiener, Keith; Wagner, John.

In: Journal of Clinical Pharmacology, Vol. 49, No. 7, 07.2009, p. 856-864.

Research output: Contribution to journalArticle

Addy, C, Assaid, C, Hreniuk, D, Stroh, M, Xu, Y, Herring, WJ, Ellenbogen, A, Jinnah, HA, Kirby, L, Leibowitz, MT, Stewart, RM, Tarsy, D, Tetrud, J, Stoch, SA, Gottesdiener, K & Wagner, J 2009, 'Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease', Journal of Clinical Pharmacology, vol. 49, no. 7, pp. 856-864. https://doi.org/10.1177/0091270009336735
Addy, Carol ; Assaid, Chris ; Hreniuk, David ; Stroh, Mark ; Xu, Yang ; Herring, W. Joseph ; Ellenbogen, Aaron ; Jinnah, H. A. ; Kirby, Louis ; Leibowitz, Mark T. ; Stewart, R. Malcolm ; Tarsy, Daniel ; Tetrud, James ; Stoch, S. Aubrey ; Gottesdiener, Keith ; Wagner, John. / Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease. In: Journal of Clinical Pharmacology. 2009 ; Vol. 49, No. 7. pp. 856-864.
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abstract = "The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selctive NMDA receptor antagonist. Patients (n = 16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P =.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P =.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.",
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