Synthesis, benzodiazepine receptor binding, and anticonvulsant activity of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitriles.
A series of oxopyridobenzothiazines (azaphenothiazines) were prepared and evaluated for binding to the benzodiazepine receptor, anticonvulsant activity in the pentylenetetrazole-induced convulsion assay, and, in two cases, ability to increase punished responding in a standard conflict test. While parent compound 1a showed binding affinity comparable to chlorodiazepoxide (CDP), its potency in the anticonvulsant assay and the anticonflict test was considerably weaker than CDP. Of the variety of derivatives synthesized, only the 7-chloro compound 1b showed receptor affinity comparable to 1a with slightly improved in vivo activity. The poor correlation between receptor binding and in vivo activity may be due to variability in absorption or pharmacological responses unrelated to affinity for the benzodiazepine receptor.
D000818:Animals; D000927:Anticonvulsants; D003220:Conflict, Psychological; D004327:Drinking Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011963:Receptors, GABA-A; D013843:Thiazines / Q000138:chemical synthesis* / Q000378:metabolism
D000927:Anticonvulsants; D011725:Pyridines; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D013843:Thiazines