MU RECEPTOR-BINDING OF SOME COMMONLY USED OPIOIDS AND THEIR METABOLITES

The binding affinity to the mu receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with H-3-DAMGO. The chemical group at position 6 of the molecule had little effect on binding (e.g. morphine-6-glucuronide K(i) = 0.6 nM; morphine = 1.2 nM), Decreasing the length of the alkyl group at position 3 decreased the K(i) values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 (e.g. hydrocodone, K(i) = 19.8 nM) had relatively weak receptor binding, whilst their O-demethylated metabolites (e.g. hydromorphone, K(i) = 0.6 nM) had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.