Morphine structure

An indication that the SAR of the narcotic antagonists was more complex than had been anticipated came from the observation of the tremendous increase in milligram potency obtained by fusing an additional bicyclic ring onto the basic morphine structure. The... 

The three-dimensional disposition of the nitrogen function to the aromatic ring allows morphine and other analgesics to bind to a pain-reducing receptor in the brain. The terminal tyrosine residue in the natural agonists Met-enkephalin and Leu-enkephalin is mimicked by portions of the morphine structure. 

Figure 1. Contemporary scheme of morphine. Friedrich Sertiirner, who first isolated this alkaloid in an impure form in 1805, did know that it was converted from the pathway of tyrosine, Tyr. The correct morphine structure was determined by Gulland and Robinson in 1923. Moreover, even 200 years after Sertiirner s isolation, scientists are still discussing the synthesis of this alkaloid from a molecular point of view. This is a good example of the scientific evolution of knowledge of alkaloids.

Certain opioids are used mainly for their antitussive effects. Such drugs generally are those with substituents on the phenolic hydroxyl group of the morphine structure. The larger the substituent, the greater the antitussive versus analgesic selectively of the drugs. 

The attempts to synthesize morphine Jed to the synthesis of its basic skeleton by Grewe, published in 1946. This work, continued by Schnider et al. (1950 1951), yielded the significant discovery that the complete morphine structure is not essential for potent analgesic activity. N-Methylmorphinan is analgesic, and (-)-3-hydroxy-N-methylmorphinan (levorphanol) is an effective therapeutic agent, more potent than morphine. 

Fig. 1 Classical derivatization of morphin. Most of the derivatives were simplifications of the morphin structure...

Fig. 2 It took more than 150 years to modify the complex morphine structure (left) to the simpler achiral morphinomi-metic fentanyl, using classical drug-design methods.

Figure 7.16. C-ring derivatives of morphine. Structures of hydromorphone (5) and oxycodone (6) from Fig. 7.1 are included for comparison. Nalmefene (64) is an antagonist, TRK-820 (65) is a K-selective agonist, and nalbuphine (66) is a mixed agonist/antagonist.

A desoxymorphine was stated by Schryver and Lees [54] to result from the reduction of a-chloromorphide with tin and hot concentrated hydrochloric acid, but a repetition of this reaction afforded only small amounts of material of different specific rotation that does not correspond to any of the known desoxymorphines, and indeed it is doubtful whether the morphine structure would survive such treatment, as even in the a —> /3-chloromorphide conversion considerable amounts of apomorphine [lxh] are formed. Wright also reported the production of a desoxymorphine on heating bromocodide with hydrobromic acid [55-58], but nothing further is known about this. 

The Knorr oxazine theory of morphine structure led to the preparation of a series of bases derived from morpholine [xxxm], so called on account of its supposed relationship to morphine [49-50]. In particular it was found that N-methylnaphthalanmorpholine [xxxrv] undergoes Hofmann degradation to a methine base [xxxv] that can be degraded further to naphthalene and /3-dimethylaminoethanol. The extraordinary ease with which this last stage takes place led Knorr to believe that an ort/to-attacbment of the nitrogen side-chain to the phenanthrene residue in the morphine alkaloids was improbable, and he accordingly advanced the structure [xxxvi] [51]). 

Eig. 1 shows a synthetic approach to the morphine structure made by Ginsburg, the correct stereo-chemical arrangement of the rings being ob. tained. The same synthesis is being carried out in the 3 4-dimethoxy series, the goal being the synthesis of dihydrothebainone. 

Butora G, Hudlicky T (1998) The story of morphine structure elucidation one hundred years of deductive reasoning. In Hudlicky T (ed) Organic synthesis theory and applications. JAI Press, Stamford, p 1... 

We turn now to more drastic alterations of the morphine structure and ask whether the complete carbon skeleton is really necessary. After all, if we could simplify the molecule, it would be easier to make in the laboratory. This in turn would allow the chemist to make analogues much more easily, and any useful compounds could be made more efficiently and cheaply. 

Other series of synthetic analgetics, intentionally or unintentionally patterned after the morphine structure, were the meperidines (including ketobemidone), the methadones (including propoxyphene), and the morphinans. These newer compounds have more or less the same disadvantages as morphine, which limits their use. Within this much investigated series of compounds, a clear-cut dissociation of the different effects of morphine proved to be impossible. 

G. Butora T. Hudlicky, The Story of Morphine Structure Elucidation One Hundred Years of Deduction Reasoning. In Organic Synthesis Theory and Application T. Hudlicky, Ed. 1998 Vol 4, p 1. 

For a number of years prior to Evans revelations, Rapoport had been involved in the development of a general methodology for the synthesis of several morphine structural analogues. These included both cis and trans 4a-aryldecahydroisoquinolines 127,65 octahydro-lH-benzofuro-[3,2-e]-isoquinolines 128,66 and novel octahydro-lH-[l]-benzopyrano-[4,3,2-e,f]-isoquinolines 129 67... 

Heteroatom directed photoarylation synthesis of a tetracyclic morphine structural analog... 

Synthesis of B/C transfused morphine structures. IV. Synthesis of B/C transisomorphine... 

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... 

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