| Width: | 250px |
| Class: | Opioid antagonist |
| Elimination Half-Life: | 12–18 hours[1] |
| Cas Number: | 49625-89-0 |
| Pubchem: | 5486554 |
| Chemspiderid: | 4588965 |
| Unii: | J0W963M37T |
| Chembl: | 140278 |
| Synonyms: | 6beta-Naltrexol; 6β-Hydroxynaltrexone; AIKO-150; 17-(Cyclopropylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol |
| 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 |
| C: | 20 |
| H: | 25 |
| N: | 1 |
| O: | 4 |
| Smiles: | C1C[C@]2([C@H]3CC4=C5[C@@]2(CCN3CC6CC6)[C@H]([C@@H]1O)OC5=C(C=C4)O)O |
| Stdinchi: | 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 |
| Stdinchikey: | 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. 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.[5] 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.
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).[6] Hence, 6β-naltrexol shows 3.5-fold selectivity for the MOR over the KOR and 100-fold selectivity for the MOR over the DOR. Relative to naltrexone, 6β-naltrexol has about half the affinity for the MOR. 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. In animal studies, 6β-naltrexol showed about 10-fold separation in potency between peripheral and central opioid antagonism, whereas naltrexone showed no separation. 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. 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]