Synthesis and pharmacological evaluation of a series of dibenzo[a,d]cycloalkenimines as N-methyl-D-aspartate antagonists.
J Med Chem
; 33(2): 789-808, 1990 Feb.
Article
de En
| MEDLINE
| ID: mdl-1688947
ABSTRACT
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 ([3H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (Ki ranging from 0.006 to 0.21 microM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (Kb ranging from 0.08 to 0.9 microM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED50 values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the Kb 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.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Composés polycycliques
/
Acide aspartique
/
Récepteurs aux neuromédiateurs
/
Imines
/
Anticonvulsivants
Limites:
Animals
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
1990
Type de document:
Article