Trans Morphine

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... 

Surprisingly, in view of the higher activity of B/C trans-morphinans over their B/C cis-counterparts (p. 136), B/C trans-morphine exhibited a lower level of antinociceptive activity than did natural morphine. The obvious difference between the two structures is the presence of the 4,5-epoxide bridge in B/C trans-morphine, which constrains the C-ring in a boat conformation (i.e., similar to the C-ring of morphine). In morphinans the C-ring is a chair structure. 

Surprise has been expressed that trans-morphine prepared in this way is a less potent analgesic than morphine, since isomorphinan derivatives (b/c trans) are more potent than derivatives of morphinan (b/c cis). This apparent anomaly may be explained by a consideration of the shape of the trans-morphine molecule,... 

Synthesisof B/C trans-fused morphine structures. III. Synthesis of B/C trans-morphine Kugita. Hiroshi Takeda, Mikio Inoue, Hirosumi Tetrahedron (1969), 25(9), 1851-62... 

Morphine - Originally B/C trans-morphine was said to be inactive, but it is now reported to be 10 as active as morphine. In this geries, potency is not reduced by methylation of the phenolic hydroxyl, and transisocodeine shows twice the potency of trans-isomorphine. 

Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J (2004) A role for proinflammatory cytokines and fractaUdne in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33) 7353-7365 Kim YS, Panganiban AT (1993) The full-length tat protein is required for TAR-independent, post-transcriptional trans activation of human immunodeficiency virus type 1 env gene expression. J Virol 67(7) 3739-3747... 

The answer is c. (Hardman, pp 543—544. Katzang, p 2533) Fentanyl is a chemical relative of meperidine that is nearly 100 times more potent than morphine. The duration of action, usually between 30 and 60 min after parenteral administration, is shorter than that of meperidine. Fentanyl citrate is only available for parenteral administration intramuscularly and intravenously. Tran sbuc cal ( lollipop ) and transdermal patches avoid first-pass metabolism of fentanyl. 

Davies, S.G., Goodwin, C.J., Pyatt, D., Smith, A.D. Palladium catalysed laboration of codeine and morphine, J. Chem. Soc., Perkin Trans. I 2001, 1413-1420. 

Coluzzi, P.H., et al. 2001. Breakthrough cancer pain A randomized trial comparing oral trans-mucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 91 123. 

The pyranopyridine ring system is also present in numerous alkaloids, two examples are ajmalicine (145) <92JCS(P1)517> and camptothecin (146) <92JA10971>. The trans 8 -aryloctahydropyrano[4,3-cjpyridine (88) and related compounds have been prepared as morphine analogues <89JCS(Pi)ii77>. 

The closure of the 4,5-epoxide bridge during synthesis of compounds with structures related to morphine has been the subject of several investigations. Schopf 50,51 was the first to achieve the closure of dihydrothebainone (13) in high yield, by dibromination followed by debromination effected with alkali. When the corresponding isomorphinan-6-one (i.e., B/C trans-dihydrothebainone) was treated in a similar manner, cyclization was less efficient/52 This pathway was employed during early syntheses of both metopon<53) (74, Scheme 2.12) (p. 36) and morphine/5 ... 

The name morphinan, suggested by Robinson, is universally used for describing members of this series together with the nonsystematic numbering illustrated in 5. Morphinans lack the furan bridge of morphine and its direct analogs and possess a B/C ring fusion that may be either cis (morphinans) or trans (isomorphinans, see p. 136). 

The morphinan nucleus possesses three chiral centers at C-9, C-14, and C-13. As two of these, C-9 and C-13, are bridged, and thus constrained, only two diastereoisomeric pairs occur. Morphinans (49) bear a cis B/C ring fusion and in this regard are related to morphine. Where the C-14 center is inverted (i.e., trans B/C fusion), compounds are known as isomorphinans (50), and these will be discussed later (p. 136). Note that in structures 49 and 50 the stereochemistry of ring C is shown in relationship to ring B. 

Morphinans are related directly to morphine in that they possess a B/C cis ring fusion. lsomorphinans, having a trans B/C fusion, may be considered as being related stereochemically to the endo-ethanotetrahydrooripavines. 

Isomorphinans possess a B/C-trans ring fusion and in this they differ from B/C cis morphine geometry. Such geometry, however, may be related stereochemically to endo-ethanotetrahydrooripavines. Opioid activity tends to be increased in B/C trans series, and a compound such as 3-hydroxy-N-methylisomorphinan is several times more potent than morphine in rat analgesic tests. 

Tramadol (25, Tramol), another cyclohexane with opioid properties, has trans l-m-methoxyphenyl,2-dimethylaminomethyl substituents and is in clinical use in West Germany. It was extensively described in a supplement of Arneimittel Forschung.(39) In animal tests its potency is closer to that of codeine than morphine and relatively high clinical doses (50-100 mg) are necessary for pain relief. Side elTects are generally minor and the compound... 

Stereochemically, the fusion of rings B/C is cis in the morphinans (as in morphine) and trans in the isomeric isomorphinans. Formation of the B/C ring junction by Gate s procedure (Chapter 3, p. 133) gives a trans closure and thus entry to isomorphinan derivatives/59 Isocyclorphan (12, 14a-H)... 

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