3-Hydroxymorphinan Explained

3-Hydroxymorphinan (3-HM), or morphinan-3-ol, is a psychoactive drug of the morphinan family.[1] It is the racemic counterpart to norlevorphanol.

The dextrorotatory stereoisomer of the compound is an active metabolite of dextromethorphan, dextrorphan, and 3-methoxymorphinan,[2] and similarly to them has potent neuroprotective and neurotrophic effects on LTS- and MPTP-treated dopaminergic neurons of the nigrostriatal pathway,[3] [4] but notably without producing any neuropsychotoxic side effects (e.g., dissociation or hallucinations) or having any anticonvulsant actions.[5] [6] It does not seem to bind to the NMDA receptor, and instead, its neuroprotective properties appear result from inhibition of glutamate release via the suppression of presynaptic voltage-dependent Ca2+ entry and protein kinase C activity.[7] In any case, as such, the compound has been investigated as a potential management of Parkinson's disease medication (antiparkinsonian agent). A prodrug, GCC1290K, has been developed on account of 3-HM's poor bioavailability (18%), and a New Drug Application has been approved for it by the United States Food and Drug Administration. It is currently undergoing clinical trials for the treatment of Parkinson's disease. It does not have a Controlled Substances Act 1970 schedule, ACSCN, or annual aggregate manufacturing quota and may not necessarily be controlled, whilst norlevorphanol is; none of the dextrorotary derivatives of the dromoran and norlevorphanol sub-families of morphinan derivatives are controlled as they do not have opioid activity but the other racemic compounds are.[8]

3-HM's levorotatory stereoisomer, norlevorphanol, in contrast to (+)-3-HM, is an opioid analgesic.[9] It was never marketed as such however, probably due to a combination of the facts that norlevorphanol has low bioavailability and that its potency is diminished compared to its N-methylated analogue levorphanol.[10]

Notes and References

  1. Book: Ganellin CR, Triggle DJ, Macdonald F . Dictionary of pharmacological agents . 29 November 2011 . 1997 . CRC Press . 978-0-412-46630-4 . 1378.
  2. Jacqz-Aigrain E, Cresteil T . Cytochrome P450-dependent metabolism of dextromethorphan: fetal and adult studies . Developmental Pharmacology and Therapeutics . 18 . 3–4 . 161–8 . 1992 . 1306804 . 10.1159/000480616.
  3. Zhang W, Qin L, Wang T . 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity . The FASEB Journal . 19 . 3 . 395–7 . March 2005 . 15596482 . 10.1096/fj.04-1586fje . free . 13513164 . etal.
  4. Zhang W, Shin EJ, Wang T . 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro . The FASEB Journal . 20 . 14 . 2496–511 . December 2006 . 17142799 . 10.1096/fj.06-6006com . free . 23032934 . etal.
  5. Shin EJ, Lee PH, Kim HJ, Nabeshima T, Kim HC . Neuropsychotoxicity of abused drugs: potential of dextromethorphan and novel neuroprotective analogs of dextromethorphan with improved safety profiles in terms of abuse and neuroprotective effects . Journal of Pharmacological Sciences . 106 . 1 . 22–7 . January 2008 . 18198471 . 10.1254/jphs.fm0070177. free .
  6. Shin EJ, Bach JH, Lee SY . Neuropsychotoxic and neuroprotective potentials of dextromethorphan and its analogs . Journal of Pharmacological Sciences . 116 . 2 . 137–48 . 2011 . 21606622 . 10.1254/jphs.11r02cr. etal. free .
  7. Lin TY, Lu CW, Wang SJ . Inhibitory effect of glutamate release from rat cerebrocortical synaptosomes by dextromethorphan and its metabolite 3-hydroxymorphinan . Neurochemistry International . 54 . 8 . 526–34 . July 2009 . 19428798 . 10.1016/j.neuint.2009.02.012 . 23428637 .
  8. Web site: Conversion Factors for Controlled Substances . Diversion Control Division . Drug Enforcement Agency, U.S. Department of Justice . 2016-02-27 . 2016-03-02 . https://web.archive.org/web/20160302162948/http://deadiversion.usdoj.gov/quotas/conv_factor/index.html . dead .
  9. Book: Dictionary of organic compounds . Chapman & Hall . London . 1996 . 0-412-54090-8 .
  10. Book: Bentham Science Publishers . Current Medicinal Chemistry . 29 November 2011 . April 1995 . Bentham Science Publishers . 425.

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