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

@article{Armstrong2013TheIV,
  title={The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity},
  author={Scott R. Armstrong and Christina B. Campbell and Carrie L. Richardson and Ross G. Vickery and Pamela R. Tsuruda and Daniel D. Long and Sharath S Hegde and David T. Beattie},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  year={2013},
  volume={386},
  pages={471-478}
}
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… 
The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist
TLDR
The in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human μ and δ, and guinea pig κ) and rodent native opioid receptors and displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets is described.
Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications
TLDR
Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL and may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids.
Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist.
TLDR
The application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of μ-opioid receptor antagonists was optimized to afford axelopran (TD-1211) 19i as a potential treatment for opioid-induced constipation is described.
Naldemedine: Peripherally-acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects.
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Improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine's analgesic effect.
Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig.
TLDR
The neurochemical coding of MOR-positive enteric neurons in the guinea pig gut is identified and differential trafficking of MOR in these neurons in response to established and putative MOR agonists is demonstrated.
Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain
TLDR
Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy.
Opioids and GI Motility—Friend or Foe?
TLDR
Novel agents, such as peripherally acting μ-opioid receptor antagonists which target the cause of OIC, show promise in the treatment of OBD and should be considered when conventional laxatives fail.
Endogenous opiates and behavior: 2013
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The in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human μ and δ, and guinea pig κ) and rodent native opioid receptors and displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets is described.
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