(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A Potent New Neuroprotectant Which Blocks N-Methyl-D-Aspartate Responses

Bl, Chenard; Bordner, Jon; Tw, Butler; Lk, Chambers; Ma, Collins; Dl, De Costa; Mf, Ducat; Ml, Dumont; Cb, Fox; Ee, Mena

doi:10.1021/jm00016a017

Cited by 169 publications

(122 citation statements)

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“…This observation is consistent with a developmental increase of release sites and of receptor density at these sites. In contrast to our expectations following reports of high expression of the NR2B subunit in the developing cortex, haloperidol and CP101,606, specific blockers of receptors comprising NR1ÏNR2B subunits (Chenard et al 1995;Ilyin et al 1996), failed to antagonize mN_EPSCs in the majority of cells in the visual cortex at P13-P15. While CP101,606 never produced significant changes in the mean mN_EPSC amplitude, haloperidol produced significant alterations in a few of the neurons tested.…”

Section: Discussioncontrasting

confidence: 99%

“…At the same time, recent studies have identified pharmacological agents which are able to antagonize in a selective manner NMDARs containing the NR1ÏNR2B subunits; these include ifenprodil (Williams, 1993), haloperidol (Ilyin, Wittermore, Guastella, Weber & Woodward, 1996) and the novel ifenprodil derivative, CP101,606 (Chenard et al 1995;Boeckman & Aizenman, 1996). Recently, antagonism of hippocampal NMDA-mediated synaptic currents by ifenprodil has been shown to be dependent on development (Kirson & Yaari, 1996), implying a developmental decrease in synaptic receptors comprising the NR2B subunit.…”

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confidence: 99%

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Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

Stocca

Vicini

1998

The Journal of Physiology

318

257

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Pharmacologically isolated miniature NMDA receptor‐mediated excitatory postsynaptic currents (mN‐EPSCs) were recorded in large visual cortical neurons in layer V of rat cortical slices. Haloperidol (100 μm) and CP101,606 (10 μm), two specific blockers of NMDA receptors comprising NR1/NR2B subunits, were tested on mN‐EPSCs in rats at postnatal days 7 and 8 (P7–P8) and P13–P15. At both ages tested, no significant effects of these drugs were seen in the whole population of neurons, although in few neurons at both ages changes in amplitude were observed with haloperidol. Other dopamine receptor antagonists, spiperone and clozapine, failed to decrease mN‐EPSCs in cortical neurons at P13–P15. CP101,606 (10 μm) significantly decreased the amplitude of evoked N‐EPSCs (eN‐EPSCs) in visual cortical slices from rats at P3–P5, a developmental stage at which mRNA studies have indicated the virtual absence of NR2A mRNA. CP101,606 failed to significantly change evoked AMPA‐mediated EPSCs at P5 and eN‐EPSCs at P7–P8 and P13–P15. NMDA receptor‐mediated currents were also studied in somatic outside‐out patches at P13–P15 with fast application of l‐glutamate (1 mm). Haloperidol (50 μm) and CP101,606 (10 μm) blocked these currents in all patches tested. The effect of CP101,606 was concentration dependent. We suggest that rather early in development synaptic receptors comprising NR1/NR2B subunits could be associated with other subunits so that blockade by haloperidol and CP101,606 is prevented. Moreover, the consistent blockade seen in outside out patches might be ascribed to the confinement of NR1/NR2B receptors to an extrasynaptic population.

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Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

Stocca

Vicini

1998

The Journal of Physiology

318

257

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“…Ketamine HCl (Hospira; Lake Forest, IL) and CP-101,606, ((1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol) mesylate salt, synthesized as described (Chenard et al, 1995) and dissolved in saline. Doses for both compounds are expressed as free base.…”

Section: Compoundsmentioning

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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“…Although, like other un-competitive NMDAR antagonists they may have some adverse effect on learning and memory, it was proved that they have a wider separation between doses that are effective in seizure or stroke models and those that disrupt learning and memory. The limited information on the novel NR2B subunit selective antagonists (Table 1) such as CP-101,606 (traxoprodil) [33,98], Ro25-6981 [59], Co-101244 [225], CI-1041 [35] and RG-1103 [18] also suggests that these drugs are better tolerated and are largely devoid of adverse CNS effects at antinociceptive doses, at least with respect to psychotomimetic, ataxic and sedative effects [19,29,35,57,146,203].…”

Section: Nr2b Subunit Selective Nmdar Antagonistsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A Potent New Neuroprotectant Which Blocks N-Methyl-D-Aspartate Responses

Cited by 169 publications

References 9 publications

Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

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

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

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