Structure-activity relationship in the effect of 1,4-benzodiazepines on morphine, aminopyrine and oestrone metabolism.

The influence of a number of 1,4-Benzodiazepines was investigated on morphine and aminopyrine metabolism and on oestrone and p-nitrophenol glucuronidation, in rat liver microsomes. Benzodiazepines inhibited in a differential degree the N-demethylase activities for morphine and aminopyrine N-demethylation as well as glucuronyltransferase activity for morphine. Oestrone glucuronyltransferase activity was markedly stimulated by certain benzodiazepines whereas p-nitrophenol glucuronidation was not altered. A structure activity relationship in the inhibition of morphine and aminopyrine metabolism by benzodiazepines was observed. In fact, the presence of halogens at C-2, a methyl group at N-1 and a methylene substituent instead of a keto group at C-3 in the benzodiazepine structure increased the inhibitory effect. The possible role of these metabolic pathways of other substituents in the benzodiazepines, is discussed.