6β-Naltrexol
Chemical compound / From Wikipedia, the free encyclopedia
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]
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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 |
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Elimination half-life | 12–18 hours[1] |
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ECHA InfoCard | 100.230.713 |
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Formula | C20H25NO4 |
Molar mass | 343.423 g·mol−1 |
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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]