6β-Naltrexol

6β-Naltrexol
Clinical data

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]
Identifiers
IUPAC name (4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7,9-triol
CAS Number	49625-89-0
PubChem CID	5486554
ChemSpider	4588965
UNII	J0W963M37T
ChEMBL	ChEMBL140278
CompTox Dashboard (EPA)	DTXSID80197942
ECHA InfoCard	100.230.713
Chemical and physical data
Formula	C₂₀H₂₅NO₄
Molar mass	343.423 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1C[C@]2([C@H]3CC4=C5[C@@]2(CCN3CC6CC6)[C@H]([C@@H]1O)OC5=C(C=C4)O)O
InChI InChI=1S/C20H25NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,14-15,18,22-24H,1-2,5-10H2/t14-,15-,18+,19+,20-/m1/s1 Key:JLVNEHKORQFVQJ-PYIJOLGTSA-N

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 (K_i) 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]

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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 RW, Dolle RE (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, et al. (December 2011). "6β-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study". Pain Medicine. 12 (12): 1727–1737. 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 Sciences. 76 (13): 1427–1437. 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". The Journal of Pharmacology and Experimental Therapeutics. 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. S2CID 195697174.