The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia.
3R-(+)-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 micrograms/ml, which decayed with a t1/2 of 56 min. The three infusion dosing regimens gave mean plasma levels over the 4 h of 11, 25 and 61 micrograms/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 micrograms/ml over the 4 h was also ineffective against the volume of infarction measured in the different brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, England.
R
R
Gill
R J
RJ
Hargreaves
J A
JA
Kemp
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018696:Neuroprotective Agents; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C084173:L 687414