Academic literature on the topic '6β-naltrexol'

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

6β-Naltrexol is the major human metabolite of naltrexone, which is an opioid receptor antagonist used in the treatment of opioid and alcohol dependence. This metabolite is thought to contribute to the pharmacological effects of naltrexone, particularly the longer duration of naltrexone compared to naloxone (the prototypical opioid receptor antagonist), but to what extent has not been fully described. 6β-Naltrexol was synthesised from naltrexone in order to conduct the studies contained in this thesis as it was not commercially available at the time. Additionally, a validated HPLC assay method needed to be developed to quantify naltrexone and 6β-naltrexol for the in vivo and in vitro studies contained within. 6β-Naltrexol was successfully synthesised, and the HPLC assay was developed for simultaneous analysis of the parent and metabolite in a number of biological fluids, and performed with a high degree of precision and accuracy throughout. The enzyme kinetics for the formation of 6β-naltrexol from naltrexone were determined in vitro in human liver cytosolic and microsomal preparations. Additionally, several compounds were tested for their likelihood of inhibition of this formation. The hepatic enzymatic formation of 6β-naltrexol from naltrexone was confined to the cytosolic and not the microsomal fraction, exhibited considerable intersubject variability and could be inhibited by a number of compounds. The most potent of these were certain steroid hormones, and naloxone. The in vivo pharmacokinetics and bioavailability of naltrexone, and the formation of 6β-naltrexol, were also assessed after oral and intravenous administration of naltrexone to healthy volunteers. Naltrexone and 6β-naltrexol were quantified in the plasma, urine and saliva of these subjects. Additionally, the correlation between 6β-naltrexol concentrations and increased subjective side-effects reported previously was assessed. As with the in vitro studies, there was a high degree of interindividual variation of pharmacokinetic parameters. It was found that saliva is possibly a better alternative to plasma in assessing naltrexone status following the 50 mg dose used clinically. There was no correlation between high biofluid concentrations of 6β-naltrexol and an increase in subjective side effects after intravenous or oral naltrexone administration. Potency studies and assessment of the duration of antagonistic activity of 6β-naltrexol were conducted in vitro in electrically-stimulated guinea pig ileum preparations (blocking the morphine-induced twitch height) and in vivo in mice (reversing morphine-induced antinociception). The potencies were compared to the parent naltrexone, and naloxone. Naltrexone was more potent than naloxone in the guinea pig ileum preparation and interestingly, 6β-naltrexol was found to be 4.5-fold more potent than naloxone, and nearly three times more potent than naltrexone in this preparation. The high potency found in the in vitro study was not reflected in the in vivo mouse study, in which 6β-naltrexol showed only 1/185th the potency of naltrexone. Whereas the in vivo potency of 6β-naltrexol was much lower than that of naltrexone or naloxone, the duration of action was much longer. The in vivo potency of 6β-naltrexol is lower than that of its parent compound naltrexone, but the longer duration of action, and the significantly higher plasma concentrations of this metabolite after an oral dose of naltrexone indicate that 6β-naltrexol will contribute significantly to the therapeutic effects of naltrexone.
Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2010