Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharmacol Exp Ther
2010 Jun 01;3333:650-62. doi: 10.1124/jpet.110.166256.
Show Gene links
Show Anatomy links
Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.
Hansen KB
,
Mullasseril P
,
Dawit S
,
Kurtkaya NL
,
Yuan H
,
Vance KM
,
Orr AG
,
Kvist T
,
Ogden KK
,
Le P
,
Vellano KM
,
Lewis I
,
Kurtkaya S
,
Du Y
,
Qui M
,
Murphy TJ
,
Snyder JP
,
Bräuner-Osborne H
,
Traynelis SF
.
???displayArticle.abstract???
N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.
Barbier,
Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.
2007, Pubmed
Barbier,
Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.
2007,
Pubmed
Bekkers,
Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus.
1993,
Pubmed
Bräuner-Osborne,
Ligands for glutamate receptors: design and therapeutic prospects.
2000,
Pubmed
Burban,
Histamine potentiates N-methyl-D-aspartate receptors by interacting with an allosteric site distinct from the polyamine binding site.
2010,
Pubmed
Cik,
Optimal expression of cloned NMDAR1/NMDAR2A heteromeric glutamate receptors: a biochemical characterization.
1993,
Pubmed
Dai,
The histamine H3 receptor antagonist clobenpropit enhances GABA release to protect against NMDA-induced excitotoxicity through the cAMP/protein kinase A pathway in cultured cortical neurons.
2007,
Pubmed
Dravid,
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block.
2007,
Pubmed
,
Xenbase
Fischer,
Effect of clobenpropit, a centrally acting histamine H3-receptor antagonist, on electroshock- and pentylenetetrazol-induced seizures in mice.
1998,
Pubmed
Haas,
Histamine in the nervous system.
2008,
Pubmed
Hansen,
Pharmacological characterization of ligands at recombinant NMDA receptor subtypes by electrophysiological recordings and intracellular calcium measurements.
2008,
Pubmed
,
Xenbase
Hawkins,
Comparison of shape-matching and docking as virtual screening tools.
2007,
Pubmed
Jorgensen,
Potential energy functions for atomic-level simulations of water and organic and biomolecular systems.
2005,
Pubmed
Kashiwagi,
Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore.
2002,
Pubmed
,
Xenbase
Leurs,
Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5-HT3 receptor revealed.
1995,
Pubmed
Lim,
Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist.
2005,
Pubmed
Lin,
Inhibition and induction of cytochrome P450 and the clinical implications.
1998,
Pubmed
Lisman,
Long-term potentiation: outstanding questions and attempted synthesis.
2003,
Pubmed
Liu,
Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow.
2001,
Pubmed
Mares,
Different effects of two N-methyl-D-aspartate receptor antagonists on seizures, spontaneous behavior, and motor performance in immature rats.
2009,
Pubmed
Mony,
Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors.
2009,
Pubmed
,
Xenbase
Mosley,
Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
2009,
Pubmed
,
Xenbase
Nacher,
The role of N-methyl-D-asparate receptors in neurogenesis.
2006,
Pubmed
Nicholls,
Variable selection and model validation of 2D and 3D molecular descriptors.
2004,
Pubmed
Peng,
Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity.
2008,
Pubmed
Perin-Dureau,
Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors.
2002,
Pubmed
,
Xenbase
Preskorn,
An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.
2008,
Pubmed
Ray,
Capsazepine protects against neuronal injury caused by oxygen glucose deprivation by inhibiting I(h).
2003,
Pubmed
Romanovsky,
The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not.
2009,
Pubmed
Tamura,
Ifenprodil prevents glutamate cytotoxicity via polyamine modulatory sites of N-methyl-D-aspartate receptors in cultured cortical neurons.
1993,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Vorobjev,
Histamine potentiates N-methyl-D-aspartate responses in acutely isolated hippocampal neurons.
1993,
Pubmed
Waxman,
N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease.
2005,
Pubmed
Williams,
Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine.
1994,
Pubmed
,
Xenbase
Witte,
Detection of multiple H3 receptor affinity states utilizing [3H]A-349821, a novel, selective, non-imidazole histamine H3 receptor inverse agonist radioligand.
2006,
Pubmed
Wlaź,
Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats.
1999,
Pubmed
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
Zanchet,
Peripheral tackykinin and excitatory amino acid receptors mediate hyperalgesia induced by Phoneutria nigriventer venom.
2003,
Pubmed
Zhang,
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.
1999,
Pubmed
