Different stereoselectivity of the enantiomers of HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) for neuroprotective and anticonvulsant actions in vivo.
HA-966 is an antagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA) receptors. Neuroprotective effects of HA-966 were determined in postnatal day (PND) 7 rats that received intrastriatal injections of NMDA (15 nmol) and then were administered either racemic HA-966, or the purified (R) or (S) enantiomer 15 min later. The (R)-enantiomer dose-dependently attenuated NMDA-induced brain injury, whereas the (S)-enantiomer was ineffective. When given intravenously to mice, racemic HA-966 and the (S)-enantiomer prevented tonic extensor seizures from low-intensity electroshock (ED50 = 13.2 and 8.8 mg/kg, respectively). Anticonvulsant effects of the (R)-enantiomer were much less potent (ED50 = 105.9 mg/kg). Ataxia measured by inverted screen fall-off was 17 times more potent with the (S)-enantiomer than with the (R)-enantiomer. Since previous published work indicates that glycine-site NMDA antagonist activity is primarily due to the (R)-enantiomer, our results suggest neuroprotective action for the (R)-enantiomer and anticonvulsant action, not related to a glycine antagonist mechanism for the (S)-enantiomer.
Vartanian
M G
MG
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI.
Taylor
C P
CP
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced / Q000517:prevention & control; D004597:Electroshock; D016202:N-Methylaspartate / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D000927:Anticonvulsants; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C001369:1-hydroxy-3-amino-2-pyrrolidone