Natural morphine

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

Scheme 11). The specific optical rotation of compound (-)-2a derived from the chiral ketone (-)-2a agreed with the reported rotation of 73 [43], showing that the absolute configuration of 73 was (4aS, 8aR) and corresponded to that of natural (-)-morphine [42]. 

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. 

Morphine, (+)-codeine, and (+)-heroin are all devoid of MHP (sc) antinociceptive activity/119 although (+)-morphine did show some central actions in rats when administered intracerebrally.(120) Compounds of the (+)-morphine series are related configurationally to (-)-sinomenine (53 of Chap. 3),(m) the absolute configuration of which has been demonstrated to be enantiomeric with that of natural (-)-morphine. 

By exploiting the work of Weller and Rapoport<56) in the natural (—)-morphine series, the NIH group was able to improve overall yields from sinomenine to unnatural opioids considerably.019 The availability of this unnatural series afforded a route to relatively large quantities of (+)-naloxone/128 also valuable for receptor studies. 

Scheme 3-54). This transformation constitutes a cascade of an intramolecular Heck insertion and subsequent heterocyclization. The initially formed arylpalladium species attacks the bridgehead position of the diene functionality in 238 to foim a JT-allylpalladium complex which is trapped by the internal nucleophilic phenol moiety (cf. Scheme 3-26). Since the starting diene 238 can be prepared in both enantiomeric forms by asymmetric reduction of a ketone, this sequence allows the preparation of both the natural morphine and its unnatural enantiomer. 

In accord with the foregoing postulates. Beckett and Casy proposed a complementary receptor site (Fig. 22-1) and suggested ways - - in which the known active molecules could be adapted to it. After their initial postulates, natural (-)-morphine was shown to be related configurationally to methadone and thiambutene, which lent weight to the hypothesis. Fundamental to their proposal was that such a receptor was essentially inflexible and that a lock-and-kcy-type. situation exLsted. Subsequently, the unnatural (-I- )-mor-phinc was synthesized and shown to be inactive." ... 

Eseroline (15), a major metabolite of (-)-physostigmine (1), was found to be an analgesic with a potency similar to that of natural morphine... 

With the advances in organic chemistry in the early decades of the century the more complex drugs began to yield their chemical structures. For example, the structure of morphine was proposed in 1923 [64] the drug was synthesized in 1952 [65], and its absolute configuration was determined in 1955 [66]. (+)-Morphine was synthesized in 1960 and was shown to differ significantly from the natural (-)-morphine in that it lacks analgesic activity, (-t)-Morphine does possess antitussive activity, albeit to a lesser extent than (-)-morphine [67]. 

In that same year, drug enforcement agencies seized only 23 metric tons of heroin worldwide.5 Heroin, formed by simple acetylation of natural morphine,6 was synthesized in an attempt to alleviate morphine addiction, but ironically, it proved to be many times more addictive, and therefore, more profitable on the illicit market. Controlling illicit... 

Products and Uses Any drug capable of producing anesthesia and analgesia. An addictive drug. There are natural (morphine, codeine) and synthetic (meperidine, ethadone, and phenazocine) forms. 

FIGURE 7.3 A structure of enkephalins (Met and Leu). The broken line indicates the alkaloid part (a derivative of tyramine) of the enkaphelins. This structural element change of -NHj group -NCHj group is also found in natural morphine. 

As the starting diene 407 can be prepared in both enantiomeric forms by asymmetric reduction of a ketone, this sequence allows one to prepare both the natural morphine and its unnatural enantiomer. 

---