CP-101,606, a potent neuroprotectant selective for forebrain neurons

Menniti, Frank S.; Chenard, B. L.; Collins, Mary; Ducat, M. F.; Shalaby, Ismail A.; White, Frost

doi:10.1016/s0014-2999(97)10092-9

Cited by 102 publications

(81 citation statements)

References 38 publications

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“…The affinity values obtained for the ifenprodil site ligands eliprodil, (Ϯ)-CP-101,606, (Ϯ)-CP-283,097, and (Ϯ)-Ro 25-6981 were very comparable to those previously reported for inhibition of [ 3 H]CP-101,606 (Menniti et al, 1997;Butler et al, 1998) …”

supporting

confidence: 85%

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Grimwood

Richards

Murray

et al. 2000

Journal of Neurochemistry

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supporting

confidence: 85%

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Grimwood

Richards

Murray

et al. 2000

Journal of Neurochemistry

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“…Ifenprodil was the first in this class of NMDA antagonists selective for the NR2B subunit of the NMDA receptor (Gotti et al, 1988;Williams, 1993) and was shown to have a novel activity-dependent mechanism of action (Kew et al, 1996. CP 101,606 is a structural analog of ifenprodil that is also a selective antagonist of NMDA NR2B subunits but, unlike ifenprodil, lacks ␣ 1 -adrenoceptor activity (Chenard et al, 1995;Menniti et al, 1997). CP 101,606 was demonstrated to protect against glutamateinduced toxicity in neuronal cultures with a potency similar to that of MK-801 (Menniti et al, 1997).…”

Section: Figmentioning

confidence: 99%

“…CP 101,606 is a structural analog of ifenprodil that is also a selective antagonist of NMDA NR2B subunits but, unlike ifenprodil, lacks ␣ 1 -adrenoceptor activity (Chenard et al, 1995;Menniti et al, 1997). CP 101,606 was demonstrated to protect against glutamateinduced toxicity in neuronal cultures with a potency similar to that of MK-801 (Menniti et al, 1997). It was also found to be neuroprotective in an acute model of focal ischemia in the cat .…”

Section: Figmentioning

confidence: 99%

Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-SelectiveN-Methyl-d-Aspartate Antagonist

Gill

Alanine²,

Bourson³

et al. 2002

J Pharmacol Exp Ther

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Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [ 3 H]dizocilpine ( 3 H-MK-801) binding in a biphasic manner with IC 50 values of 0.002 and 97 M for the high-and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C ϩ NR2B subunits with an IC 50 of 0.003 M and those containing NR1C ϩ NR2A subunits with an IC 50 of Ͼ100 M, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C ϩ NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC 50 values of 0.68 and 0.06 M, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED 50 ϭ 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED 50 of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.Native NMDA receptors are composed of an NR1 subunit (can occur as eight different splice variants), which combines with NR2A-D subunits to form heteromeric receptors (for reviews see McBain and Mayer, 1994;Kemp and Kew, 1998). NMDA receptors are thought to be tetramers that are composed of two NR1 and two NR2 subunits (Laube et al., 1998), which is compatible with earlier electrophysiological evidence demonstrating that NMDA receptor activation requires occupation of two independent glycine binding sites and two independent glutamate sites (Benveniste and Mayer, 1991;Clements and Westbrook, 1991). The glutamate and glycine binding sites are believed to be located on the NR2 and NR1 subunits, respectively (Wafford et al., 1995;Hirai et al., 1996;Laube et al., 1997;Anson et al., 1998). However, the proposed tetrameric stoichiometry of NMDA receptor remains controversial because evidence also exists for a pentameric structure (for review see Kemp and Kew, 1998).In the adult rodent and human brain the NR1 subunit is widely distributed throughout the brain, whereas the NR2 subunits are expressed in a distinct spatio-temporal manner (Watanabe et al., 1993;Monyer et al., 1994;Rigby et al., 1996;Wenzel et al., 1997). The predominant NR2 subunits in the forebrain are NR2A and NR2...

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“…Summarization studies in animal models have provided a large body of evidence that glutamate accumulation in the synaptical fissure is a main cause of cell death. Reduction of glutamate levels or neurotransmission via different pharmacological agents can ameliorate such effects (43,(46)(47)(48).…”

Section: Nmda-receptor Antagonistsmentioning

confidence: 99%

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

Beauchamp

Mutlak

Smith

et al. 2008

Mol Med

154

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Traumatic brain injury (TBI) represents a major health care problem and a significant socioeconomic challenge worldwide. In the United States alone, approximately 1.5 million patients are affected each year, and the mortality of severe TBI remains as high as 35%-40%. These statistics underline the urgent need for efficient treatment modalities to improve posttraumatic morbidity and mortality. Despite advances in basic and clinical research as well as improved neurological intensive care in recent years, no specific pharmacological therapy for TBI is available that would improve the outcome of these patients. Understanding of the cellular and molecular mechanisms underlying the pathophysiological events after TBI has resulted in the identification of new potential therapeutic targets. Nevertheless, the extrapolation from basic research data to clinical application in TBI patients has invariably failed, and results from prospective clinical trials are disappointing. We review the published prospective clinical trials on pharmacological treatment modalities for TBI patients and outline future promising therapeutic avenues in the field.

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CP-101,606, a potent neuroprotectant selective for forebrain neurons

Cited by 102 publications

References 38 publications

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-SelectiveN-Methyl-d-Aspartate Antagonist

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

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CP-101,606, a potent neuroprotectant selective for forebrain neurons

Cited by 102 publications

References 38 publications

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [3H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [3H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-SelectiveN-Methyl-d-Aspartate Antagonist

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

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Product

Resources

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Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [³H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes