Diastereoisomeric N-tetrahydrofurfurylnoroxymorphones with opioid agonist-antagonist properties

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Abstract
The 2 diastereoisomeric N-tetrahydrofurfurylnoroxymorphones and their hydrochlorides were prepared and studied pharmacologically. The N-(R)-tetrahydrofurfuryl derivative 1a was an opioid agonist-antagonist and the N-(S)-tetrahydrofurfuryl derivative 1b a pure antagonist. As an analgesic, 1a was 25 times more potent than morphine, but it did not show morphine-like side-effects in mice. In withdrawn morphine-dependent rhesus monkeys, 1a only partially suppressed abstinence. Its therapeutic ratio was exceptionally favorable compared with those of morphine and pentazocine. As antagonists, 1a and 1b have comparable potencies of 0.25 and 0.20 of that of nalorphine, respectively, in vivo. In vitro 1a was 28 times (guinea pig ileum) or 6.5 times (mouse vas deferens) more potent than 1b. The antagonist properties of 1a and 1b were not anticipated according to known structure-activity relationships.

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