6β-Naltrexol - Misplaced Pages

(Redirected from Naltrexol) Chemical compound

Pharmaceutical compound

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
Identifiers
IUPAC name (4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuroisoquinoline-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
3D model (JSmol)	Interactive image
SMILES C1C2(3CC4=C52(CCN3CC6CC6)(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. 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. In addition to being an active metabolite of naltrexone, 6β-naltrexol was itself studied for the treatment of opioid-induced constipation. 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 (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). 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.

6β-Naltrexol is said to have very limited capacity to cross the blood–brain barrier. 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.

References

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