The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2013-06, Vol.386 (6), p.471-478
• Main Authors: Armstrong, Scott R., Campbell, Christina B., Richardson, Carrie L., Vickery, Ross G., Tsuruda, Pamela R., Long, Daniel D., Hegde, Sharath S., Beattie, David T.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analgesics, Opioid - antagonists & inhibitors; Analgesics, Opioid - pharmacology; Animals; Benzamides - administration & dosage; Benzamides - pharmacology; Biomedical and Life Sciences; Biomedicine; Central Nervous System - drug effects; Central Nervous System - metabolism; Dogs; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Male; Mice; Morphine - antagonists & inhibitors; Morphine - pharmacology; Naltrexone - administration & dosage; Naltrexone - pharmacology; Narcotic Antagonists - administration & dosage; Narcotic Antagonists - pharmacology; Neurosciences; Original Article; Pain - drug therapy; Pharmacology/Toxicology; Piperidines - administration & dosage; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome - etiology; Tropanes - administration & dosage; Tropanes - pharmacology
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-013-0844-5

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.