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Vol. 283, Issue 3, 1285-1292, 1997
Pharma Division, Preclinical CNS Research, F. Hoffmann-La Roche
Ltd., CH-4070 Basel, Switzerland
The interaction of Ro 25-6981 with N-methyl-D-aspartate
(NMDA) receptors was characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H-MK-801
binding to rat forebrain membranes in a biphasic manner with
IC50 values of 0.003 µM and 149 µM for high- (about
60%) and low-affinity sites, respectively. NMDA receptor subtypes
expressed in Xenopus oocytes were blocked with
IC50 values of 0.009 µM and 52 µM for the subunit
combinations NR1C & NR2B and NR1C & NR2A, respectively, which indicated
a >5000-fold selectivity. Like ifenprodil, Ro 25-6981 blocked NMDA
receptor subtypes in an activity-dependent manner. Ro 25-6981
protected cultured cortical neurons against glutamate toxicity (16 h
exposure to 300 µM glutamate) and combined oxygen and glucose
deprivation (60 min followed by 20 h recovery) with
IC50 values of 0.4 µM and 0.04 µM, respectively. Ro
25-6981 was more potent than ifenprodil in all of these tests. It
showed no protection against kainate toxicity (exposure to 500 µM for 20 h) and only weak activity in blocking Na+ and
Ca++ channels, activated by exposure of cortical neurons to
veratridine (10 µM) and potassium (50 mM), respectively. These
findings demonstrate that Ro 25-6981 is a highly selective,
activity-dependent blocker of NMDA receptors that contain the NR2B
subunit.
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