az értekezés - Semmelweis Egyetem Doktori Iskola

8. Summary
Morphine and other opiates are the most effective analgesics and are widely used in
clinical practice; the analgesic effect of all known painkillers is compared to morphine.
Despite its widespread use, the high incidence of unwanted side-effects, most notably
tolerance and dependence liability have encouraged the development of novel analgesic
opioids that possess analgesic activity similar to that of morphine but exhibit less or no
dangerous adverse effects. Among the newly identified compounds, metabolites have been
in the center of attention for some time. The two most effective metabolite conjugates are
morphine-6-O-sulfate and morphine-6-O-glucuronide: their analgesic effect is superior to
that of morphine. Furthermore, favorable pharmacokinetic properties make these
conjugates potential new analgesic drug candidates.
In my thesis I review the relevant synthetic methods and the report preparation of
various naturally occurring and semi-synthetic sulfate ester and glucoside derivatives of
morphine congeners. We synthesized the sulfate esters of morphine, dihydromorphine,
codeine, dihydrocodeine and their methylated quaternary derivatives. We prepared 14-
methoxycodeine, 14-methoxymorphine and their sulfate esters. The synthesis of sulfate
monoesters was accomplished by pyridine-SO3 complex, whereas diesters were prepared
by direct sulfation using sulphuric acid/DCC. Glucoside conjugates were synthesized by
means of Koenigs-Knorr reaction. The appropriately protected morphine derivatives were
dissolved in benzene, the glucosylation was then carried out by α-acetobromo-glucose in
the presence of silver carbonate activator. The crude products were purified by column
chromatography. The protecting groups were hydrolyzed by lithium hydroxide. Detailed
spectroscopic analyses (NMR, MS, CD, UV/VIS) were carried out for the synthesized
compounds. We also developed a quick and facile HPLC method for the separation of
morphine and codeine glucosides from their parent compounds and glucuronide conjugates.
Pharmacological testing was carried out for selected compounds by the Department of
Pharmacology and Pharmacotherapy at SE. The most effective of the studied compounds is
14-methoxy-morphine-6-O-sulfate: it possesses longer duration of action and more than
2000-fold increased analgesic potency than that of morphine and is effective when
administered peripherally. The substance is a promising potential future analgesic drug.
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