Synthesis and pharmacological evaluation of a series of dibenzo[a,d]cycloalkenimines as N-methyl-D-aspartate antagonists
| Autor: | W J, Thompson, P S, Anderson, S F, Britcher, T A, Lyle, J E, Thies, C A, Magill, S L, Varga, J E, Schwering, P A, Lyle, M E, Christy |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Models
Molecular N-Methylaspartate Chemical Phenomena Stereochemistry In Vitro Techniques Binding Competitive Receptors N-Methyl-D-Aspartate Ion Channels In vivo Drug Discovery Animals Potency Polycyclic Compounds Binding site Cerebral Cortex Aspartic Acid Chemistry Antagonist Rats Inbred Strains Biological activity Rats Receptors Neurotransmitter Membrane Drug Design Thermodynamics Molecular Medicine NMDA receptor Anticonvulsants Imines Enantiomer |
| Zdroj: | Journal of Medicinal Chemistry. 33:789-808 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of 73 dibenzo[a,d]cycloalkenimines were synthesized and evaluated for their ability to displace (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([ 3 H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (K i ranging from 0.006 to 0.21 μM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (K b ranging from 0.08 to 0.9 μM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED 50 values ranges from 0.22 to 7.76 mg/kg and correlated reasonably well with the K b determination. In the dibenzo[a,d]cyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher levels of biological activity. While substitution at the 3-position of (+)-10 with electronegative atoms generally increased in vitro activity, a loss of potency relative to (+)-10 (MK-801) was observed in vivo for all of the compounds tested |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|