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7 Medicinal chemistryOpioids
The parent compound is morphine, which has a complex ring structure. The impor-
tant features include the phenolic hydroxyl (−OH) group in the 3 position, which is
different from the cyclohexanol−OH group in the 6 position. The former is essential
for activity in morphine-like opioids, but the latter is not; the 6-glucuronide metabo-
lite of morphine is active, the 3- glucuronide is not. Modifications include acetylation
at both the 3 and 6 positions to the pro-drug diamorphine; this increases lipid sol-
ubility and reduces onset time as only de-acetylation at the 3 position is essential
for activity. Codeine is methylated through the 3 hydroxyl group increasing lipid
solubility but reducing activity. The 6-keto derivatives are more active. The second
important feature is the amine group, which is also necessary for receptor binding.
Substitutions here can result in antagonists, such as naloxone. Not all rings are nec-
essary for activity, with the phenolic ring being most important. Loss of various rings
results in drugs such as fentanyl and its derivatives.