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Titolo:
STATE-DEPENDENT NMDA RECEPTOR ANTAGONISM BY RO-8-4304, A NOVEL NR2B SELECTIVE, NONCOMPETITIVE, VOLTAGE-INDEPENDENT ANTAGONIST
Autore:
KEW JNC; TRUBE G; KEMP JA;
Indirizzi:
F HOFFMANN LA ROCHE & CO LTD,PRECLIN CNS RES,DIV PHARMA CH-4070 BASELSWITZERLAND F HOFFMANN LA ROCHE & CO LTD,PRECLIN CNS RES,DIV PHARMA CH-4070 BASELSWITZERLAND
Titolo Testata:
British Journal of Pharmacology
fascicolo: 3, volume: 123, anno: 1998,
pagine: 463 - 472
SICI:
0007-1188(1998)123:3<463:SNRABR>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-ASPARTATE RECEPTOR; RAT-BRAIN; MOLECULAR CHARACTERIZATION; HIPPOCAMPAL-NEURONS; BINDING-SITES; MESSENGER-RNA; IFENPRODIL; SUBUNIT; GLYCINE; EXPRESSION;
Keywords:
NMDA RECEPTOR ANTAGONISTS; NEUROPROTECTION; GLUTAMATE RECEPTORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
J.N.C. Kew et al., "STATE-DEPENDENT NMDA RECEPTOR ANTAGONISM BY RO-8-4304, A NOVEL NR2B SELECTIVE, NONCOMPETITIVE, VOLTAGE-INDEPENDENT ANTAGONIST", British Journal of Pharmacology, 123(3), 1998, pp. 463-472

Abstract

1 Subunit-selective blockade of N-methyl-D-aspartate (NMDA) receptorsprovides a potentially attractive strategy for neuroprotection in theabsence of undesirable side effects. Here, we describe a novel NR2B-selective NMDA antagonist, ydro-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 ratcultured 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 mu M NMDA responses with IC(50)s of 2.3 and 0.36 mu M, respectively. Currents elicited by 1 mu M NMDA were slightly potentiated in the presence of 10 mu MRo 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 02:03:21