Vol. 280, Issue 1, 357-365, 1997

N-Methyl-D-aspartate Antagonist Activity of - and -Sulfallorphans¹

Vijay K. Shukla and Simon Lemaire

Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8 M5

Resolved equatorial () and axial () forms of S-allylmorphinans, -sulfallorphan and -sulfallorphan, were tested for their ability to compete with the binding of phencyclidine and sigma receptor ligands to mouse brain membranes and to antagonize N-methyl-D-aspartate (NMDA)-induced convulsions in mice. - and -sulfallorphans displayed distinct binding affinities for phencyclidine and sigma sites, inhibiting the binding of [³H]-(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([³H]MK-801) with K_i values of 2.32 and 0.13 µM and that of [³H](+)-pentazocine with K_i values of 1.97 and 1.61 µM, respectively. Intracerebroventricular administration of these compounds in mice caused dose-dependent inhibitions of NMDA-induced convulsions, but did not affect convulsions induced by (R,S)--amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. - and -sulfallorphans blocked the convulsive activity of NMDA (1 nmol/mouse; intracerebroventricular) with ED₅₀ values of 0.48 and 0.015 nmol/mouse, as compared with 0.55, 0.039 and 0.013 nmol/mouse for dextrorphan, MK-801 and (±)3-(2-carboxypiperazine-4yl)propyl-1-proprionic acid, respectively. The structurally related compound, dextrallorphan, significantly but less potently blocked NMDA-induced convulsions (ED₅₀, 2.68 nmol/mouse). At the protective doses, - and -sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that - and -sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.