The in vitro pharmacology of the peripherally restricted opioid receptor antagonists,alvimopan, ADL 08-0011 and methylnaltrexone

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human μ opioid receptors (pK _i values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the μ receptor over human δ and guinea pig κ opioid receptors. ADL 08-0011 had the highest μ receptor selectivity. With respect to their μ opioid receptor functional activity (³⁵S]GTPγS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the μ opioid agonist, endomorphin-1 (pA ₂ values of 9.6, 9.4, and 7.6, respectively) and by U69593, a κ opioid agonist (pA ₂ values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with κ opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity. The clinical significance of the data from this study remains to be determined.