Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:007581 (NR2B)
 2,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 microM for the high- and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C + NR2B subunits with an IC(50) of 0.003 microM and those containing NR1C + NR2A subunits with an IC(50) of >100 microM, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C + 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 microM, 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) = 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.
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PMID:Pharmacological characterization of Ro 63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist. 1218 50

The ionotropic glutamate NMDA/NR2B receptor and its interaction with ifenprodil-like noncompetitive ligands were investigated by a combined ligand-based and target-based approach. First, we generated 3D pharmacophore hypotheses and identified common chemical features that are shared by a training set of well-known NR2B antagonists. The binding mode of the most representative ligand was also studied by molecular docking. Because the docking results and the suggested 3D pharmacophore model were in good agreement, we obtained new information about the NR2B ifenprodil site. The best pharmacophoric hypothesis was used as a query for in silico screening; this allowed the identification of new "hit". We synthesized "hit-compound" analogues, and some of the molecules showed significant activity both in binding and functional assay as well as in vivo anticonvulsant efficacy in DBA/2 mice. The most active derivatives also exhibited neuroprotective effects against glutamate-induced toxicity in HCN-1A cells.
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PMID:Computational studies to discover a new NR2B/NMDA receptor antagonist and evaluation of pharmacological profile. 1876 69

DBA/2J mouse has been used as a model for spontaneous secondary glaucoma. Here, we investigated changes in expression of NMDA receptor (NMDAR) subunits and Cdk5/p35/NMDAR signaling in retinas of DBA/2J mice using Western blot technique. The protein levels of NR1 and NR2A subunits in retinas of DBA/2J mice at all ages (6-12 months) were not different from those in age-matched C57BL/6 mice. In contrast, the protein levels of NR2B subunits, in addition to age-dependent change, significantly increased with elevated intraocular pressure (IOP) in DBA/2J mice at 6 and 9 months as compared with age-matched controls. Moreover, expression of Cdk5, p35 and ratio of p-NR2A(S1232)/NR2A progressively increased with time in both strains, suggestive of activated Cdk5/p35 signaling pathway. However, the changes in these proteins were in the same levels in both strain mice, except a significant increase of p35 proteins at 6 months in DBA/2J mice. Meanwhile, the protein levels of Brn-3a, a retinal ganglion cell (RGC) maker, remarkably decreased at 9-12 months in DBA/2J mice, which was in parallel with the changes of NR2B expression. Our results suggest that elevated IOP-induced increase in expression of NR2B subunits of NMDARs may be involved in RGC degeneration of DBA/2J mice.
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PMID:Enhanced expression of NR2B subunits of NMDA receptors in the inherited glaucomatous DBA/2J mouse retina. 2417 1

Repeated administration of ethanol (EtOH) in mice leads to behavioural sensitization, a progressive increase in locomotor activity. Since not all mice sensitize equally to EtOH, the objective of the present study was to determine whether variability in this response is associated with altered subunit gene expression of the N-methyl-d-aspartate receptor (NMDAR), a primary target of EtOH. We examined NR1, NR2A, and NR2B expression throughout the brain during the development phase of EtOH sensitization, as well as after a 14 day withdrawal period. Male DBA/2J mice received 5-6 injections of EtOH (2.2g/kg, i.p.) or saline (SAL) and were categorized as high- (HS) or low-sensitized (LS) on the basis of locomotor activity scores after the final injection. NMDAR subunits were analyzed by in situ hybridization in brains removed either immediately following the final EtOH injection or 14 days thereafter. At the end of development phase, LS mice showed increased NR2A expression in several brain areas compared to saline controls. LS animals also had greater NR1 expression in the nucleus accumbens core (+11%, p=0.05) and shell (+14%, p=0.04) compared to HS mice, and increased NR2B expression in hippocampal CA1 (+20%, p=0.05) relative to saline-treated animals. High-sensitized mice showed increased NR2A expression in the bed nucleus of the stria terminalis when compared to controls (+54%, p=0.02). No differences in gene expression between the treatment groups were seen 14 days after the final injection. These findings suggest that region-specific NMDAR subunits may play an important role in the variability associated with the induction of EtOH sensitization. Low-sensitized mice may be more sensitive to the NMDAR inhibitory effects of EtOH, with the NR1 and NR2A subunits potentially playing a key role in the failure to sensitize upon repeated EtOH exposure.
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PMID:Altered NMDA receptor subunit gene expression in brains of mice showing high vs. low sensitization to ethanol. 2431 34