Effects of a NR2B selective NMDA glutamate antagonist, CP‐101,606, on dyskinesia and parkinsonism

Nutt, John G.; Gunzler, Steven A.; Kirchhoff, Trish; Hogarth, Penelope; Weaver, John C.; Krams, Michael; Jamerson, Brenda D.; Menniti, Frank S.; Landen, Jaren W.

doi:10.1002/mds.22169

Cited by 125 publications

(81 citation statements)

References 27 publications

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“…Recent studies of the low-trapping NMDA channel blocker lanicemine showed an enhanced gamma-band power both in rats and humans, but it did not induce psychotomimetic effects in patients (Sanacora et al, 2014). On the other hand, in humans, CP-101,606 was observed to evoke dissociative effects in some patients at higher doses (Nutt et al, 2008;Preskorn et al, 2008). It is not known at present whether the lack effects of CP-101,606 on gamma power in rats translates to humans.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Nagy

Stoiljković

Menniti

et al. 2015

Neuropsychopharmacol

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Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory-evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5-30 min (drug-on) and 5-6 h (drug-off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the drug-off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma-band power during the drug-on period. Although both drugs affected delta power, these changes did not correlate with increase in AEPs in the drug-off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid-onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.

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Section: Discussionmentioning

confidence: 99%

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Nagy

Stoiljković

Menniti

et al. 2015

Neuropsychopharmacol

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“…In humans, the effects reported are largely descriptive and include anecdotal reports of impaired delayed word recall memory in healthy humans and abnormal thinking (including dissociation and amnesia) in Parkinson's Disease patients following IV infusion of CP101,606 (Merchant et al, 1999;Nutt et al, 2008). Unfortunately, the effect of CP101,606 infusion on cognition in patients with treatment-resistant depression was not reported.…”

Section: Introductionmentioning

confidence: 99%

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

Weed

Bookbinder

Polino

et al. 2015

Neuropsychopharmacol

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Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a nonspecific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

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“…The drug also reduced the maximum severity of levodopainduced dyskinesia approximately by 30% but it did not improve Parkinsonism. Side effects were dose-related dissociation and amnesia [234], although in another study the drug was well tolerated, although no efficacy was seen in severe TBI [235].…”

Section: Taxoprodilmentioning

confidence: 96%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Effects of a NR2B selective NMDA glutamate antagonist, CP‐101,606, on dyskinesia and parkinsonism

Cited by 125 publications

References 27 publications

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

Ion Channels as Drug Targets in Central Nervous System Disorders

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