Morphine-6-glucuronide

Morphine-6-glucuronide
Other names M6G
Identifiers
CAS number	20290-10-2 N
PubChem	5360621
ChemSpider	4514548 Y
MeSH	Morphine-6-glucuronide
ChEMBL	CHEMBL1330 Y
Jmol-3D images	Image 1
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
InChI InChI=1S/C23H27NO9/c1-24-7-6-23-10-3-5-13(31-22-17(28)15(26)16(27)19(33-22)21(29)30)20(23)32-18-12(25)4-2-9(14(18)23)8-11(10)24/h2-5,10-11,13,15-17,19-20,22,25-28H,6-8H2,1H3,(H,29,30)/t10-,11+,13-,15-,16-,17+,19-,20-,22+,23-/m0/s1 Y Key: GNJCUHZOSOYIEC-GAROZEBRSA-N Y InChI=1/C23H27NO9/c1-24-7-6-23-10-3-5-13(31-22-17(28)15(26)16(27)19(33-22)21(29)30)20(23)32-18-12(25)4-2-9(14(18)23)8-11(10)24/h2-5,10-11,13,15-17,19-20,22,25-28H,6-8H2,1H3,(H,29,30)/t10-,11+,13-,15-,16-,17+,19-,20-,22+,23-/m0/s1 Key: GNJCUHZOSOYIEC-GAROZEBRBC
Properties
Molecular formula	C23H27NO9
Molar mass	461.46 g/mol
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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 UDP-Glucuronosyltransferase-2B7 (UGT2B7). M6G can accumulate to toxic levels in kidney failure.^[1][2]

The μ-opioid receptor subtype 3 appears to be activated (agonized) by morphine-6β-glucuronide but not morphine itself.^[3] This finding is also true of certain heroin metabolites (6-MAM) but not morphine proper.

History of discovery

This analgesic activity of M6G (in animals) was first noted by Yoshimura.^[4]

Subsequent work at St Bartholomew's Hospital, London in the 1980s,^[5] using a sensitive and specific HPLC assay,^[6] accurately defined for the first time the metabolism of morphine, and the abundance of this metabolite (along with morphine-3-glucuronide^[7] 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.^[1] Accumulation of M3G and M6G also decrease with return of renal function after renal transplantation.^[2]

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.^[8]

See also

• Morphine-N-oxide
• Codeine-6-glucuronide

References

1. ^ ^{a b} Osborne, R J; Joel, SP; Slevin, ML (1986). "Morphine intoxication in renal failure: the role of morphine-6-glucuronide". Br Med J 292 (6535): 1548–9. doi:10.1136/bmj.292.6535.1548. PMC 1340555. PMID 3087512. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1340555. 
2. ^ ^{a b} Osborne, R; Joel, S; Grebenik, K; Trew, D; Slevin, M (1993). "The pharmacokinetics of morphine and morphine glucuronides in kidney failure". Clin Pharmacol Ther 54 (2): 158–67. doi:10.1038/clpt.1993.127. PMID 8354025. 
3. ^ Brown GP, Yang K, King MA, et al (July 1997). "3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist". FEBS Lett. 412 (1): 35–8. doi:10.1016/S0014-5793(97)00710-2. PMID 9257684. 
4. ^ Hidetoshi, Y; Oguri, K; Tsukamoto, H (1969). "Metabolism of drugs. LXII. Isolation and identification of morphine glucuronides in urine and bile of rabbits". Biochem Pharmacol 18 (2): 279–86. doi:10.1016/0006-2952(69)90205-6. PMID 5778147. 
5. ^ Osborne, R; Joel, S; Trew, D; Slevin, M (1990). "Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide". Clin Pharmacol Ther. 47 (1): 12–9. doi:10.1038/clpt.1990.2. PMID 2295214. 
6. ^ Joel, S; Osborne, RJ; Slevin, ML (1988). "An improved method for the simultaneous determination of morphine and its principal glucuronide metabolites". J Chromatogr 430 (2): 394–9. doi:10.1016/S0378-4347(00)83176-X. PMID 3235512. 
7. ^ 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.
8. ^ Osborne, R; Thompson, P; Joel, S; Trew, D; Patel, N; Slevin, M (1992). "The analgesic activity of morphine-6-glucuronide". Br J Clin Pharmacol 34 (2): 130–8. PMC 1381529. PMID 1419474. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1381529.