(+)-Naloxone

(+)-Naloxone

Systematic (IUPAC) name
(1R,5S,13S,17R)- 10,17-dihydroxy- 4-(prop-2-en-1-yl)- 12-oxa- 4-azapentacyclo [9.6.1.01,13.05,17.07,18] octadeca- 7(18),8,10-trien- 14-one
Clinical data
MedlinePlus	a601092
Pregnancy cat.	?
Legal status	Uncontrolled
Identifiers
ATC code	?
PubChem	CID 5491858
ChemSpider	4590735 N
Chemical data
Formula	C19H21NO4
Mol. mass	327.374 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m0/s1 N Key:UZHSEJADLWPNLE-PIKADFDJSA-N N
N(what is this?)  (verify)

(+)-Naloxone (dextro-naloxone) is a drug which is the "unnatural" enantiomer of the opioid antagonist drug (-)-naloxone. Unlike "normal" naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.^[1][2]

Relation of TLR4 to opioid drugs

Both "normal" and "unnatural" enantiomers of various opioid analgesic drugs including morphine, meperidine, fentanyl, methadone and buprenorphine, as well as some otherwise inactive metabolites like morphine-3-glucuronide, have been found to act as agonists of TLR4, and chronic use of these drugs consequently causes constant low-level release of TNF-α and IL-1β as well as other downstream effects. This is thought to be involved in various adverse properties of opioid analgesic drugs, such as loss of efficacy with extended use and the associated development of tolerance and dependence, as well as the development of side effects such as hyperalgesia and allodynia, which can cause long-term use of opioid analgesics to not only fail to treat neuropathic pain, but ultimately exacerbate it.^[3][4]

Applications of (+)-naloxone and related drugs

Several opioid antagonist drugs were found to act as antagonists for TLR4, including naloxone and naltrexone. However it was found that not only the "normal" (-) enantiomers, but also the "unnatural" (+) enantiomers of these drugs acted as TLR4 antagonists (though (+)-nalmefene was inactive). Since (+)-naloxone and (+)-naltrexone lack affinity for opioid receptors, they do not block the effects of opioid analgesic drugs, and so can be used to counteract the TLR4-mediated side effects of opioid agonists without affecting analgesia.^[5] (+)-Naloxone was also found to be neuroprotective,^[6][7] and both (+)-naloxone and (+)-naltrexone are effective in their own right at treating symptoms of neuropathic pain in animal models.^[8] However (+)-naloxone was also found to reduce the effects of stimulant drugs,^[9][10] suggesting additional actions beyond TLR4 antagonism (possibly as a sigma receptor antagonist),^[11] that might potentially result in unwanted side effects or drug interactions.

See also

• Dextromethorphan
• Eritoran
• Methylnaltrexone

References

1. ^ Wu HE, Thompson J, Sun HS, Terashvili M, Tseng LF (September 2005). "Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord". The Journal of Pharmacology and Experimental Therapeutics 314 (3): 1101–8. doi:10.1124/jpet.105.087130. PMID 15901793. 
2. ^ Watkins LR, Hutchinson MR, Rice KC, Maier SF (November 2009). "The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia". Trends in Pharmacological Sciences 30 (11): 581–91. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2783351. 
3. ^ Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR (January 2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity 24 (1): 83–95. doi:10.1016/j.bbi.2009.08.004. PMC 2788078. PMID 19679181. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2788078. 
4. ^ Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR (May 2010). "Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences". Neuroscience 167 (3): 880–93. doi:10.1016/j.neuroscience.2010.02.011. PMID 20178837. 
5. ^ Wu HE, Sun HS, Cheng CW, Terashvili M, Tseng LF (November 2006). "dextro-Naloxone or levo-naloxone reverses the attenuation of morphine antinociception induced by lipopolysaccharide in the mouse spinal cord via a non-opioid mechanism". The European Journal of Neuroscience 24 (9): 2575–80. doi:10.1111/j.1460-9568.2006.05144.x. PMID 17100845. 
6. ^ Liu B, Du L, Hong JS (May 2000). "Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation". The Journal of Pharmacology and Experimental Therapeutics 293 (2): 607–17. PMID 10773035. 
7. ^ Liu Y, Qin L, Wilson BC, An L, Hong JS, Liu B (September 2002). "Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons". The Journal of Pharmacology and Experimental Therapeutics 302 (3): 1212–9. doi:10.1124/jpet.102.035956. PMID 12183682. 
8. ^ Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". The European Journal of Neuroscience 28 (1): 20–9. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470. PMID 18662331. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2588470. 
9. ^ Chatterjie N, Alexander GJ, Sechzer JA, Lieberman KW (June 1996). "Prevention of cocaine-induced hyperactivity by a naloxone isomer with no opiate antagonist activity". Neurochem. Res. 21 (6): 691–3. PMID 8829141. 
10. ^ Chatterjie N, Sechzer JA, Lieberman KW, Alexander GJ (February 1998). "Dextro-naloxone counteracts amphetamine-induced hyperactivity". Pharmacology, Biochemistry, and Behavior 59 (2): 271–4. doi:10.1016/S0091-3057(97)00528-5. PMID 9476969. 
11. ^ Wu HE, Hong JS, Tseng LF (October 2007). "Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse". European Journal of Pharmacology 571 (2-3): 145–51. doi:10.1016/j.ejphar.2007.06.012. PMC 2080825. PMID 17617400. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2080825.