[3H]alvimopan binding to the μ opioid receptor:: Comparative binding kinetics of opioid antagonists

Alvimopan is a novel peripheral mu opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. We hypothesized that the long duration of action of alvimopan might be related to a slower dissociation rate from the mu opioid receptor compared to other shorter acting antagonists. The dissociation rate of alvimopan from the mu opioid receptor (t(1/2)=30-44 min) was comparable to that of the long acting partial agonist buprenorpbine (t(1/2)=44 min), but was slower than those of the antagonists naloxone (t(1/2)=0.82 min) and N-methylnaltrexone (t(1/2)=0.46 min). Also, increases in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone and methylnaltrexone, were observed upon preincubation with the mu opioid receptor. Consistent with its long duration of action, alvimopan has a slow dissociation rate from the g opioid receptor compared to other shorter acting antagonists and may be more potent if administered prior to dosing with exogenous opioids. (c) 2005 Elsevier B.V. All rights reserved.