title: The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity.
abstract: The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.
authors.affiliation: Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. sarmstrong@theravance.com
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: Christina B
authors.initials: CB
authors.lastname: Campbell
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Richardson
authors.forename: Ross G
authors.initials: RG
authors.lastname: Vickery
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tsuruda
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Long
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
authors.forename: David T
authors.initials: DT
authors.lastname: Beattie
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C585268:3-(8-(2-(cyclohexylmethyl(2,3-dihydroxypropionyl)amino)ethyl)-8-azabicyclo(3.2.1)oct-3-yl)benzamide; C585269:ADL 08-0011; D000701:Analgesics, Opioid; D001549:Benzamides; D009292:Narcotic Antagonists; D010880:Piperidines; D014326:Tropanes; D009271:Naltrexone; C419502:alvimopan; D009020:Morphine