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We studied the substrate specificity of some opioid derivatives of 5,9-dimethyl-2′-hydroxybenzomorphan [1], composed of A, B, and D ring-systems of morphine, for human UDP-glucuronosyltransferase 2B7 (hUGT2B7), a typical glucuronidation enzyme to morphine and for bovine microsomal UGT. The group of nitrogen atom on the D ring (pyperidine ring) in [1] was modified with alkyl, alkenyl, alkynyl and aralkyl hydrocarbon substituents. hUGT2B7 did not react with the compounds with methyl and isopropyl groups on the nitrogen atom, but reacted with those having longer alkyl substituents of more than 3 carbon chains. Substances with alkenyl and isobutyl substituents are the best substrates (the Km value, 15 and 25 µM, respectively). Opioids with alkynyl and aralkyl hydrocarbon substituents are of low affinity (the Km value, 119 and 542 µM, respectively). Meanwhile, bovine enzyme did not react with opioid substances having methyl and isopropyl groups, like hUGT2B7. Bovine enzyme reacted well with opioid substances with alkenyl and alkynyl substituents on the same level as alkyl substituents. Thus, a clear difference between human UGT2B7 and bovine microsomal UGT was found in the reactivity of alkynyl group and this comes from species specificity. For development of effective opioid drugs, these results suggest that opioid compounds with short carbon substituents are better to maintain the effective level in the blood for a longer time, with low glucuronidation activity, as well as maintaining the analgesic potency of each drug.

Substrate Specificity of Opioid Compounds to UDP-Glucuronosyltransferase (UGT), hUGT2B7 and Bovine Microsomal UGT