Article date: February 1998
By: James N C. Kew, Gerhard Trube, John A. Kemp, in Volume 123, Issue 3, pages 463-472
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 NR1001/NR2B than NR1001/NR2A receptors.
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.
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 μM NMDA responses with IC50s of 2.3 and 0.36 μM, respectively. Currents elicited by 1 μM NMDA were slightly potentiated in the presence of 10 μM Ro 8‐4304, and Ro 8‐4304 binding slowed the rate of glutamate dissociation from NMDA receptors.
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.
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.
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 NR1001/NR2B than NR1001/NR2A receptors.
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.
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 μM NMDA responses with IC50s of 2.3 and 0.36 μM, respectively. Currents elicited by 1 μM NMDA were slightly potentiated in the presence of 10 μM Ro 8‐4304, and Ro 8‐4304 binding slowed the rate of glutamate dissociation from NMDA receptors.
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.
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.
British Journal of Pharmacology (1998) 123, 463–472; doi:10.1038/sj.bjp.0701634
DOI: 10.1038/sj.bjp.0701634
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