(+)-Naloxone

Drug 477200552 (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 plusnaloxone_structure.png skin-invert-image a601092 Investigational correct CAS 65700-73-4 correct FDA 54MPN7YN98 5491858 correct drugbank correct chemspider 4590735 19 21 1 4 C=CCN1CC[C@@]23[C@H]4C(=O)CC[C@@]2([C@@H]1CC5=C3C(=C(C=C5)O)O4)O correct chemspider 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 correct chemspider UZHSEJADLWPNLE-PIKADFDJSA-N (+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (−)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, Iijima I, Minamikawa J, Jacobson AE, Brossi A, Rice KC Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone Journal of Medicinal Chemistry 21 4 398–400 April 1978 206698 10.1021/jm00202a018 but instead has been discovered to act as a selective antagonist of Toll-like receptor 4 (TLR4). 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. Wu HE, Thompson J, Sun HS, Terashvili M, Tseng LF 7190985 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 September 2005 15901793 10.1124/jpet.105.087130 Many opioid drugs activate TLR4, leading to several long-term side effects. Watkins LR, Hutchinson MR, Rice KC, Maier SF The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia Trends in Pharmacological Sciences 30 11 581–91 November 2009 19762094 2783351 10.1016/j.tips.2009.08.002 Potential applications Counteracting TLR4 activation by opioids Relation with opioids Both active and inactive 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. 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 6 Evidence that opioids may have toll-like receptor 4 and MD-2 effects Brain, Behavior, and Immunity 24 1 83–95 January 2010 19679181 2788078 10.1016/j.bbi.2009.08.004 Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR 6 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 May 2010 20178837 2854318 10.1016/j.neuroscience.2010.02.011 Several opioid antagonist drugs were found to act as antagonists for TLR4, including naloxone and naltrexone. However it was found that not only the (−) enantiomers, but also the (+) 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. Wu HE, Sun HS, Cheng CW, Terashvili M, Tseng LF 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 November 2006 17100845 10.1111/j.1460-9568.2006.05144.x 43870764 free For example, the reinforcing effects of opioid drugs is mediated by TLR4 and (+)-naloxone deminishes that effect. Hutchinson MR, Northcutt AL, Hiranita T, Wang X, Lewis SS, Thomas J, van Steeg K, Kopajtic TA, Loram LC, Sfregola C, Galer E, Miles NE, Bland ST, Amat J, Rozeske RR, Maslanik T, Chapman TR, Strand KA, Fleshner M, Bachtell RK, Somogyi AA, Yin H, Katz JL, Rice KC, Maier SF, Watkins LR 6 Opioid activation of toll-like receptor 4 contributes to drug reinforcement The Journal of Neuroscience 32 33 11187–200 August 2012 22895704 3454463 10.1523/JNEUROSCI.0684-12.2012 Neuroprotective agent (+)-Naloxone was also found to be neuroprotective due to reduction of TLR4-mediated inflammation, Liu B, Du L, Hong JS 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 May 2000 10773035 http://jpet.aspetjournals.org/content/293/2/607 Liu Y, Qin L, Wilson BC, An L, Hong JS, Liu B 42487051 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 September 2002 12183682 10.1124/jpet.102.035956 and both (+)-naloxone and (+)-naltrexone are effective in their own right at treating symptoms of neuropathic pain in animal models. Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR 6 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 July 2008 18662331 2588470 10.1111/j.1460-9568.2008.06321.x Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR 6 (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats The Journal of Pain 13 5 498–506 May 2012 22520687 3348259 10.1016/j.jpain.2012.02.005 Additional actions However (+)-naloxone was also found to reduce the hyperactive effects of stimulant drugs, Chatterjie N, Alexander GJ, Sechzer JA, Lieberman KW 23866510 Prevention of cocaine-induced hyperactivity by a naloxone isomer with no opiate antagonist activity Neurochemical Research 21 6 691–3 June 1996 8829141 10.1007/BF02527726 Chatterjie N, Sechzer JA, Lieberman KW, Alexander GJ 31087300 Dextro-naloxone counteracts amphetamine-induced hyperactivity Pharmacology, Biochemistry, and Behavior 59 2 271–4 February 1998 9476969 10.1016/S0091-3057(97)00528-5 suggesting additional actions beyond TLR4 antagonism (possibly as a sigma receptor antagonist), Wu HE, Hong JS, Tseng LF 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 October 2007 17617400 2080825 10.1016/j.ejphar.2007.06.012 that might potentially result in unwanted side effects or drug interactions. See also Dextromethorphan Eritoran Methylnaltrexone References Category:Experimental drugs Category:Allylamines