Interactions of narcotics an their antagonists with human serum esterase. IX: structure-activity relationships of...

The interaction of 21 morphinan and 25 morphine derivatives with human serum esterase was examined. The behavior of these drugs closely parallels that of their simpler analogues, benzomorphans, studied previously: all have affinity for an allosteric modifying site at which agonists accelerate enzyme action and, except for 6-ketodihydromorphines, all are also competitive inhibitors of the enzyme. The results suggest that both ring C of morphinans and morphines and the furan ring of morphines contribute to binding to the allosteric site; so does increase in the size of the N-alkyl group, but alkylation at C-6 or C-7 is unfavorable for such binding. A hydroxyl group at C-6 or C-14, or a methoxyl group at C-3 are also unfavorable. As with benzomorphans, we found that the natural (--)-morphine configuration is more sensitive than its optical antipode to structural influences on its affinity for the allosteric site.