Abstract

Resolved equatorial (α) and axial (β) forms ofS-allylmorphinans, α-sulfallorphan and β-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. α- and β-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)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. α- and β-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, α- and β-sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that α- and β-sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.