6β-Naltrexol

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]

Other names6beta-Naltrexol; 6β-Hydroxynaltrexone; AIKO-150; 17-(Cyclopropylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol

Drug classOpioid antagonist

Elimination half-life12–18 hours^[1]

CAS Number

• 49625-89-0

Quick facts Clinical data, Other names ...

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

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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]