6β-Naltrexol
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| Other names | 6beta-Naltrexol; 6β-Hydroxynaltrexone; AIKO-150; 17-(Cyclopropylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol |
| Drug class | Opioid antagonist |
| Pharmacokinetic data | |
| Elimination half-life | 12–18 hours[1] |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.230.713 |
| Chemical and physical data | |
| Formula | C20H25NO4 |
| Molar mass | 343.423 g·mol−1 |
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6β-Naltrexol, or 6β-hydroxynaltrexone (developmental code name AIKO-150), is a peripherally-selective opioid receptor antagonist related to naltrexone.[2][3] It is a major active metabolite of naltrexone formed by hepatic dihydrodiol dehydrogenase enzymes.[2][3] With naltrexone therapy, 6β-naltrexol is present at approximately 10- to 30-fold higher concentrations than naltrexone at steady state due to extensive first-pass metabolism of naltrexone into 6β-naltrexol.[4] In addition to being an active metabolite of naltrexone, 6β-naltrexol was itself studied for the treatment of opioid-induced constipation.[2][5][6] It was found to be effective and well-tolerated, and did not precipitate opioid withdrawal symptoms or interfere with opioid pain relief, but development was not further pursued.[2][5][6]
6β-Naltrexol binds to the opioid receptors with affinity (Ki) values of 2.12 nM for the μ-opioid receptor (MOR), 7.24 nM for the κ-opioid receptor (KOR), and 213 nM for the δ-opioid receptor (DOR).[5] Hence, 6β-naltrexol shows 3.5-fold selectivity for the MOR over the KOR and 100-fold selectivity for the MOR over the DOR.[5] Relative to naltrexone, 6β-naltrexol has about half the affinity for the MOR.[1] In contrast to naltrexone, 6β-naltrexol is a neutral antagonist of the MOR (as opposed to an inverse agonist) and can antagonize the actions of both agonists and inverse agonists at the receptor.[7]
6β-Naltrexol is said to have very limited capacity to cross the blood–brain barrier.[8] However, 6β-naltrexol is still able to cross into the brain and produce central opioid receptor antagonism at sufficient levels.[5] In animal studies, 6β-naltrexol showed about 10-fold separation in potency between peripheral and central opioid antagonism, whereas naltrexone showed no separation.[5] Because it is a MOR neutral antagonist and hence does not reduce basal MOR signaling, 6β-naltrexol shows much lower potential for producing opioid withdrawal symptoms than naltrexone at doses achieving similar central opioid blockade in animal studies.[5][7] Due to the very high levels of 6β-naltrexol that occur during naltrexone therapy, 6β-naltrexol may contribute to the central opioid receptor antagonism of naltrexone.[9]
See also
References
- ^ a b Dean R, Bilsky EJ, Negus SS (12 March 2009). Opiate Receptors and Antagonists: From Bench to Clinic. Springer Science & Business Media. pp. 269–. ISBN 978-1-59745-197-0.
- ^ a b c d Smith HS (21 February 2013). Opioid Therapy in the 21st Century. Oxford University Press. pp. 69–. ISBN 978-0-19-984497-5.
- ^ a b Cote CJ, Lerman J, Anderson BJ (2013). A Practice of Anesthesia for Infants and Children: Expert Consult - Online and Print. Elsevier Health Sciences. pp. 148–. ISBN 978-1-4377-2792-0.
- ^ Davis MP, Glare PA, Hardy J (28 May 2009). Opioids in Cancer Pain. Oxford University Press. pp. 41–. ISBN 978-0-19-923664-0.
- ^ a b c d e f g Hipkin, R. William; Dolle, Roland E. (2010). "Opioid Receptor Antagonists for Gastrointestinal Dysfunction". Annual Reports in Medicinal Chemistry. Vol. 45. Elsevier. pp. 142–155. doi:10.1016/S0065-7743(10)45009-5. ISBN 9780123809025. ISSN 0065-7743.
- ^ a b Yancey-Wrona J, Dallaire B, Bilsky E, Bath B, Burkart J, Webster L, Magiera D, Yang X, Phelps M, Sadee W (December 2011). "6β-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study". Pain Med. 12 (12): 1727–37. doi:10.1111/j.1526-4637.2011.01279.x. PMID 22123184.
- ^ a b Sadée W, Wang D, Bilsky EJ (February 2005). "Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities". Life Sci. 76 (13): 1427–37. doi:10.1016/j.lfs.2004.10.024. PMID 15680308.
- ^ Oberdick J, Ling Y, Phelps MA, Yudovich MS, Schilling K, Sadee W (July 2016). "Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice". J Pharmacol Exp Ther. 358 (1): 22–30. doi:10.1124/jpet.115.231902. PMC 4931874. PMID 27189967.
- ^ Gonzalez JP, Brogden RN (March 1988). "Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence". Drugs. 35 (3): 192–213. doi:10.2165/00003495-198835030-00002. PMID 2836152.
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