4,5/3-Epoxymorphinan analgesics

Morphine has a B/C cis ring fusion, and formal inversion of the C-14 chiral center leads to a series of analgesically active B/C trans-4,5-epoxymor-phinans. Japanese workers013,114) have described a preparation of B/C trans-4,5-epoxymorphinans by the hydroboration of 8-dihydrodesoxycodeine, and the same group has synthesized B/C trans-morphine and B/C trans-codeine... 

Opioid receptor affinity labels have been reported for other narcotic analgesics, for example, piperidines, 293 294 benzomorphans, 295 296 and mor-phinans, 297,298 and the topic is further discussed in Chapter 13 (p. 445). Not only is the oxo-function in the 4,5-epoxymorphinan C-ring available for ready elaboration, but C-6 substituents, although they affect agonist potency, do not impair unduly receptor affinity. 299 301 ... 

Substitution at C-6 was not necessary for good levels of analgesic activity, for desomorphine (83, R = Me) was 10 times more potent than morphine. However, some 6-azido-4,5-epoxymorphinans (e.g., 89) were 50 x morphine as analgesics in humans, and although the same level of activity was seen in corresponding 14-OH derivatives, the fact that the presence of a 14-OH did not increase the level of potency indicates that in this case the 6- and 14-substituents affect receptor binding differently. 

The influence of a 14-OH substituent in 4,5-epoxymorphinans is reflected in the morphinan series Antagonist activities in N-CPM, N-CBM, and N-allyl series are increased relative to corresponding 14-H analogs, and they exert relatively weak analgesic actions This applies, regardless of the 14-OH configuration (i e, morphinan or isomorphinan) The introduction of a 6-oxo function into such structures enhances agonist responses... 

Naturally occurring and semisynthetic epoxymorphinans (1,2) (Fig. 1) have proved to be of the utmost importance as analgesics for the treatment of moderate to severe pain as a result of their agonist actions at the mu opioid receptor (MOR). 

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