Morphine-6-glucuronide: Difference between revisions

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|ImageFile=Morphine 6-glucuronide.png

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|OtherNames=M6G

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| CASNo = <!-- blanked - oldvalue: 20290-10-2 -->

| ChEMBL = 1330

| SMILES = O=C(O)[C@H]6O[C@@H](O[C@H]1/C=C\[C@@H]5[C@@]24c3c(ccc(O)c3O[C@@H]12)C[C@H]5N(C)CC4)[C@H](O)[C@@H](O)[C@@H]6O

| MeSHName=Morphine-6-glucuronide

|Section2= {{Chembox Properties

| Formula=C₂₃H₂₇NO₉

| MolarMass=461.46 g/mol

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|Section3= {{Chembox Hazards

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'''Morphine-6-glucuronide''' (M6G) is a major active [[metabolite]] of [[morphine]], and as such is the [[molecule]] responsible for much of the pain-relieving effects of morphine (and thus [[heroin]]). M6G is formed from morphine by the enzyme [[UGT2B7|UDP-Glucuronosyltransferase-2B7]] (UGT2B7). M6G can accumulate to toxic levels in [[kidney failure]].<ref name=Osborne1986/><ref name=Osborne1993/>

The [[mu Opioid receptor|μ-opioid receptor]] subtype 3 appears to be activated (agonized) by morphine-6β-glucuronide but not morphine itself.<ref>{{cite journal |author=Brown GP, Yang K, King MA, ''et al'' |title=3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist |journal=FEBS Lett. |volume=412 |issue=1 |pages=35–8 |year=1997 |month=July |pmid=9257684 |doi=10.1016/S0014-5793(97)00710-2 |url=}}</ref> This finding is also true of certain heroin metabolites (6-MAM) but not morphine proper.

Subsequent work at [[St Bartholomew's Hospital]], London in the 1980s,<ref>{{Cite journal | doi = 10.1038/clpt.1990.2 | title = Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide | journal = Clin Pharmacol Ther. | year = 1990 | volume = 47 | pages = 12–9 | pmid = 2295214 | last1 = Osborne | first1 = R | last2 = Joel | first2 = S | last3 = Trew | first3 = D | last4 = Slevin | first4 = M | issue = 1}}</ref> using a sensitive and specific [[High performance liquid chromatography|HPLC assay]],<ref>{{cite journal | title = An improved method for the simultaneous determination of morphine and its principal glucuronide metabolites| journal = J Chromatogr| year = 1988 | volume = 430 | pages = 394–9 | doi = 10.1016/S0378-4347(00)83176-X | author = Joel, S | pmid = 3235512 | last2 = Osborne | first2 = RJ | last3 = Slevin | first3 = ML | issue = 2}}</ref> accurately defined for the first time the metabolism of morphine, and the abundance of this metabolite (along with [[morphine-3-glucuronide]]<ref>[http://dmd.aspetjournals.org/cgi/content/abstract/19/6/1087 ''Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney.'' JT Van Crugten, BC Sallustio, RL Nation and AA Somogyi. Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia. ]</ref> and morphine-3,6-diglucuronide, both considered inactive metabolites).

It was postulated that [[renal impairment]] would result in accumulation of the renally-excreted active agent M6G, leading to potentially fatal toxicity such as respiratory depression. The frequent use of morphine in critically ill patients, and the common occurrence of [[renal failure]] in this group implied that M6G accumulation could be a common, but previously unanticipated problem. The first studies demonstrated massive levels of M6G in 3 patients with renal failure, which resolved as [[kidney]] function returned.<ref name=Osborne1986>{{cite journal | title = Morphine intoxication in renal failure: the role of morphine-6-glucuronide | journal = Br Med J | year = 1986 | volume = 292 | pages = 1548–9 | doi = 10.1136/bmj.292.6535.1548 | author = Osborne, R J | pmid = 3087512 | last2 = Joel | first2 = SP | last3 = Slevin | first3 = ML | issue = 6535 | pmc = 1340555}}</ref> Accumulation of M3G and M6G also decrease with return of renal function after [[renal transplantation]].<ref name=Osborne1993>{{cite journal | doi = 10.1038/clpt.1993.127 | title = The pharmacokinetics of morphine and morphine glucuronides in kidney failure | journal = Clin Pharmacol Ther | year = 1993 | volume = 54 | pages = 158–67 | pmid = 8354025 | last1 = Osborne | first1 = R | last2 = Joel | first2 = S | last3 = Grebenik | first3 = K | last4 = Trew | first4 = D | last5 = Slevin | first5 = M | issue = 2}}</ref>

A key step in defining the importance of M6G in man came in 1992 when the substance was artificially synthesised and administered to patients with pain, the majority of whom described pain relief.<ref>{{cite journal | title = The analgesic activity of morphine-6-glucuronide | journal = Br J Clin Pharmacol | year = 1992 | volume = 34 | pages = 130–8 | pmid = 1419474 | last1 = Osborne | first1 = R | last2 = Thompson | first2 = P | last3 = Joel | first3 = S | last4 = Trew | first4 = D | last5 = Patel | first5 = N | last6 = Slevin | first6 = M | issue = 2 | pmc = 1381529}}</ref>

{{reflist}}

[[Category:Glucuronides]]

[[Category:Morphinans]]

[[Category:Mu-opioid agonists]]

[[ru:Морфин-6-глюкуронид]]