N-methyl-D-aspartate antagonist activity of alpha- and beta-sulfallorphans.

Abstract

Resolved equatorial (alpha) and axial (beta) forms of S-allylmorphinans, alpha-sulfallorphan and beta-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. alpha- and beta-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 Ki values of 2.32 and 0.13 microM and that of [3H](+)-pentazocine with Ki values of 1.97 and 1.61 microM, 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)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. alpha- and beta-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 (ED60, 2.68 nmol/mouse). At the protective doses, alpha- and beta-sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that alpha- and beta-sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.

• Authors: V K Shukla, S Lemaire
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 280 Issue 1 Pg. 357-65 (Jan 1997) ISSN: 0022-3565 [Print] United States
• PMID: 8996216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Excitatory Amino Acid Antagonists
• Morphinans
• Piperazines
• Receptors, N-Methyl-D-Aspartate
• Receptors, Phencyclidine
• Receptors, sigma
• Dizocilpine Maleate
• 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid

Topics

• Animals
• Anticonvulsants (pharmacology)
• Dizocilpine Maleate (pharmacology)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (pharmacology)
• Male
• Mice
• Morphinans (pharmacology)
• Motor Activity (drug effects)
• Piperazines (pharmacology)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Receptors, Phencyclidine (metabolism)
• Receptors, sigma (metabolism)
• Structure-Activity Relationship