title: The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone.
abstract: 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 mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS 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 mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa 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 kappa 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.
authors.affiliation: Department of Pharmacology, Theravance Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. dbeattie@theravance.com
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
authors.forename: M
authors.initials: M
authors.lastname: Cheruvu
authors.forename: N
authors.initials: N
authors.lastname: Mai
authors.forename: M
authors.initials: M
authors.lastname: O'Keefe
authors.forename: S
authors.initials: S
authors.lastname: Johnson-Rabidoux
authors.forename: C
authors.initials: C
authors.lastname: Peterson
authors.forename: E
authors.initials: E
authors.lastname: Kaufman
authors.forename: R
authors.initials: R
authors.lastname: Vickery
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D011994:Recombinant Proteins; D014162:Transfection
chemical_list: C585269:ADL 08-0011; D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010880:Piperidines; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; C105293:endomorphin 1; C032257:methylnaltrexone; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C419502:alvimopan; D009020:Morphine; C045444:U 69593