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.
D000632:Aminopyrine / Q000378:metabolism*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D004970:Estrone / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D009596:Nitrophenols / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D005965:Glucuronates; D009596:Nitrophenols; D000632:Aminopyrine; D001569:Benzodiazepines; D004970:Estrone; D009020:Morphine; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase; C024836:4-nitrophenol