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State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist.
Br J Pharmacol. 1998 Feb; 123(3):463-72.BJ

Abstract

1. Subunit-selective blockade of N-methyl-D-aspartate (NMDA) receptors provides a potentially attractive strategy for neuroprotection in the absence of undesirable side effects. Here, we describe a novel NR2B-selective NMDA antagonist, 4-¿3-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxy-propoxy ¿-benzamide (Ro 8-4304), which exhibits >100 fold higher affinity for recombinant NR1(001)/NR2B than NR1(001)/NR2A receptors. 2. Ro 8-4304 is a voltage-independent, non-competitive antagonist of NMDA receptors in rat cultured cortical neurones and exhibits a state-dependent mode of action similar to that described for ifenprodil. 3. The apparent affinity of Ro 8-4304 for the NMDA receptor increased in an NMDA concentration-dependent manner so that Ro 8-4304 inhibited 10 and 100 microM NMDA responses with IC50s of 2.3 and 0.36 microM, respectively. Currents elicited by 1 microM NMDA were slightly potentiated in the presence of 10 microM Ro 8-4304, and Ro 8-4304 binding slowed the rate of glutamate dissociation from NMDA receptors. 4. These results were predicted by a reaction scheme in which Ro 8-4304 exhibits a 14 and 23 fold higher affinity for the activated and desensitized states of the NMDA receptor, respectively, relative to the agonist-unbound resting state. Additionally, Ro 8-4304 binding resulted in a 3 4 fold increase in receptor affinity for glutamate site agonists. 5. Surprisingly, whilst exhibiting a similar affinity for NR2B-containing NMDA receptors as ifenprodil, Ro 8-4304 exhibited markedly faster kinetics of binding and unbinding to the NMDA receptor. This spectrum of kinetic behaviour reveals a further important feature of this emerging class of NR2B-selective compounds.

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Authors+Show Affiliations

Kew JN
Pharma Division, Preclinical CNS Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Trube G
No affiliation info available
Kemp JA
No affiliation info available

MeSH

AnimalsBenzamidesEvoked PotentialsExcitatory Amino Acid AntagonistsGlutamic AcidIon Channel GatingKineticsPiperidinesProtein BindingPyridinesRatsReceptors, N-Methyl-D-AspartateXenopus laevis

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9504387

Citation

Kew, J N., et al. "State-dependent NMDA Receptor Antagonism By Ro 8-4304, a Novel NR2B Selective, Non-competitive, Voltage-independent Antagonist." British Journal of Pharmacology, vol. 123, no. 3, 1998, pp. 463-72.
Kew JN, Trube G, Kemp JA. State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist. Br J Pharmacol. 1998;123(3):463-72.
Kew, J. N., Trube, G., & Kemp, J. A. (1998). State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist. British Journal of Pharmacology, 123(3), 463-72.
Kew JN, Trube G, Kemp JA. State-dependent NMDA Receptor Antagonism By Ro 8-4304, a Novel NR2B Selective, Non-competitive, Voltage-independent Antagonist. Br J Pharmacol. 1998;123(3):463-72. PubMed PMID: 9504387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist. AU - Kew,J N, AU - Trube,G, AU - Kemp,J A, PY - 1998/3/21/pubmed PY - 1998/3/21/medline PY - 1998/3/21/entrez SP - 463 EP - 72 JF - British journal of pharmacology JO - Br J Pharmacol VL - 123 IS - 3 N2 - 1. Subunit-selective blockade of N-methyl-D-aspartate (NMDA) receptors provides a potentially attractive strategy for neuroprotection in the absence of undesirable side effects. Here, we describe a novel NR2B-selective NMDA antagonist, 4-¿3-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxy-propoxy ¿-benzamide (Ro 8-4304), which exhibits >100 fold higher affinity for recombinant NR1(001)/NR2B than NR1(001)/NR2A receptors. 2. Ro 8-4304 is a voltage-independent, non-competitive antagonist of NMDA receptors in rat cultured cortical neurones and exhibits a state-dependent mode of action similar to that described for ifenprodil. 3. The apparent affinity of Ro 8-4304 for the NMDA receptor increased in an NMDA concentration-dependent manner so that Ro 8-4304 inhibited 10 and 100 microM NMDA responses with IC50s of 2.3 and 0.36 microM, respectively. Currents elicited by 1 microM NMDA were slightly potentiated in the presence of 10 microM Ro 8-4304, and Ro 8-4304 binding slowed the rate of glutamate dissociation from NMDA receptors. 4. These results were predicted by a reaction scheme in which Ro 8-4304 exhibits a 14 and 23 fold higher affinity for the activated and desensitized states of the NMDA receptor, respectively, relative to the agonist-unbound resting state. Additionally, Ro 8-4304 binding resulted in a 3 4 fold increase in receptor affinity for glutamate site agonists. 5. Surprisingly, whilst exhibiting a similar affinity for NR2B-containing NMDA receptors as ifenprodil, Ro 8-4304 exhibited markedly faster kinetics of binding and unbinding to the NMDA receptor. This spectrum of kinetic behaviour reveals a further important feature of this emerging class of NR2B-selective compounds. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/9504387/State_dependent_NMDA_receptor_antagonism_by_Ro_8_4304_a_novel_NR2B_selective_non_competitive_voltage_independent_antagonist_ L2 - https://doi.org/10.1038/sj.bjp.0701634 DB - PRIME DP - Unbound Medicine ER -
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