Morphine synthetic analogues

Cyclo(His-D-Leu) acts as a hydrolytic catalyst. Cyclo(Leu-Gly) blocks the development of (1) physical dependence on morphine, (2) tolerance to the pharmacological effects of /3-endorphin, (3) tolerance to haloperidol-induced catalepsy and hypothermia, and (4) dopaminergic supersensitivity after chronic morphine administration. Cyclo(Tyr-Arg), a synthetic analogue of kyortorphin (an endogenous analgesic peptide), and its A-methyl tyrosine derivatives are more potent than kyotorphin in the mouse tail pressure test. ... 

The drugs naltrexone and nalbuphine are semi-synthetic analogues of the analgesic morphine. Morphine is a good painkiller, but has some unpleasant side effects, the most serious of which is the likelihood of becoming addicted. 

In attempts to discover chugs demonstrating fewer undesirable side effects than morphine, many synthetic analogues have been prepared. Some of these are shown in Table 1. 

A review of the use of opium and of morphine and its synthetic analogues has been published.377... 

The 4,5-epoxide bridge defines the morphine-based analogues. Removal of the epoxide is not trivial, and analogues lacking it are derived from synthetic methods. These analogues are discussed in greater detail in Section 11.5. 

Benzomorphans - clinically used synthetic analogues of morphine. A short review for nonpharmacologists Palmer, David C. Strauss, Michael J. 

The first syathesis of morphine, and therefore also codeiae, was completed ia 1956 (58). Although an additional twelve or so syntheses have been reported siace then, isolation of morphine remains more important than any synthetic process. However, synthetic endeavors continue to demonstrate new synthetic tools and capabiUties and to conduct the search for modified analogues that retain the analgesic properties of morphine but are nonaddicting. 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

The dangers of dependency and addiction clearly preclude the use of such compounds as morphine, meperidine, and methadone as treatment for diarrhea. Antidiarrheal specificity therefore is of paramount importance in choosing among the synthetic opioids and their analogues (e.g., diphenoxylate and loperamide). 

TABLE 1. SYNTHETIC MORPHINE ANALOGUES Name Molecular formula Structure... 

A fair number of carbo-ammonium dicationic species and related systems have been reported. These distonic superelectrophiles have been directly observed and shown to be useful in synthetic methodologies. For example, the acid-catalyzed Grewe-cyclization is a well-known reaction used in the preparation of morphine analogues.37 The conversion involves formation of the distonic superelectrophile (102) from an appropriate... 

Perhaps it may be possible to use this diversity and selectivity of action to develop new synthetic opiates that will have therapeutic advantages over morphine and its analogues which, in one form or another, have been used by mankind for nearly 2000 years. 

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