Synthesis and opioid activities of some naltrexone oxime ethers

A series of alkyl, cycloalkyl, aryl, and aralkyl ethers of naltrexone oxime was prepared. The compounds were examined in binding assays for μ, δ and κ opioid receptor affinity. In addition, the, naltrexone oxime ethers were studied in animal models that measure opioid agonist and antagonist activity. These studies led to the discovery of several compounds, notably phenethyl 3e and phenylpropyl 3f ethers of naltrexone, which have a 10-fold increase in potency at the κ opioid receptor with potent μ and κ agonist properties in vivo.