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3 R-(+)- cis-4-Methyl-HA966 (L-687,414) is a novel and selective, low intrinsic activity, partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Thus, while it acts primarily to block NMDA receptor function in the presence of glycine, it fails to produce a complete block of NMDA receptor activation. In this study, we have investigated its neuroprotective effects in a rat model of focal ischaemia, involving permanent occlusion of the left middle cerebral artery. L-687,414 was administered as a bolus dose of 17.6 mg/kg i.v. straight after the occlusion or as a bolus dose + infusion for 4 h. The doses of L-687,414 used for the infusion studies were 7 mg/kg i.v. +7 mg/kg/h, 14 mg/kg + 14 mg/kg/h, or 30 mg/kg + 30 mg/kg/h. The 17.6-mg/kg dose gave an estimated peak plasma level of 24 μg/ml, which decayed with a t I/2  of 56 min. The three infusion dosing regimens gave mean plasma levels over the 4 h of 11, 25, and 61 μg/ml plasma, respectively. The 17.6-mg/kg dose of L-687,414 gave no significant protection against the volume of hemispheric, cortical, or caudate damage when compared with the control group of animals. The lowest infusion dosing regimen of L-687,414 which gave a plasma level of 11 μg/ml over the 4 h was also ineffective against the volume of infarction measured in the different brain regions. The middle dose of L-687,414 (25 μg/ml) gave a highly significant reduction in the volume of ischaemic brain damage for the hemisphere and cerebral cortex, volumes of ischaemic tissue being reduced by 34 and 41% compared with saline-treated animals, respectively. The highest plasma concentration of L-687,414 (61 μg/ml) resulted in a 18% reduction in the volume of hemispheric damage and a 21% reduction in the volume of cortical damage, which were significant. The reduced protection afforded by the highest dose of L-687,414 may be due to the slight hypotensive (MABP decreased by 13–16 mm Hg) effect produced by this dose. There was no protection seen against the volume of damage in the caudate nucleus for any of the doses of L-687,414 tested. Thus, L-687,414 was effective in producing neuroprotection in this model of ischaemia at doses that do not affect MABP or have any other of the adverse effects associated with neuroprotective doses of NMDA receptor ion channel blockers such as MK-801.

The Neuroprotective Effect of the Glycine Site Antagonist 3R-(+)-cis-4-Methyl-HA966 (L-687,414) in a Rat Model of Focal Ischaemia