LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders

@article{RorickKehn2014LY2456302IA,
  title={LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders},
  author={Linda M. Rorick-Kehn and Jeffrey M. Witkin and Michael A. Statnick and Elizabeth Lutz Eberle and Jamie H. McKinzie and Steven D. Kahl and Beth M. Forster and Conrad J. Wong and Xia Li and Robert S. Crile and David B. Shaw and Allison E. Sahr and Benjamin L. Adams and Steven Quimby and Nuria D{\'i}az and Alma Jim{\'e}nez and Concepci{\'o}n Pedregal and Charles Mitch and Kelly L. Knopp and Wesley H. Anderson and Jeffrey W. Cramer and David McKinzie},
  journal={Neuropharmacology},
  year={2014},
  volume={77},
  pages={131-144}
}
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106 Citations
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Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence
TLDR
Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist, and is therefore feasible for further studies in cocaine-dependent persons.
Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice
Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders.
TLDR
While animal studies have indicated that compounds of this structural class are capable of normalizing withdrawal signs in animal models of cocaine and alcohol dependence and reducing cocaine andalcohol intake/seeking, additional studies are needed to determine the value of these second generation KOR antagonists in treating mood disorders and substance use disorders in humans.
Computational insights into different inhibition modes of the κ-opioid receptor with antagonists LY2456302 and JDTic
TLDR
To investigate the inhibition mechanism of the κ-OR induced by the two ligands, unbiased molecular dynamics and well-tempered metadynamics simulations were performed and a strong but single interaction mode was found to be responsible for the adverse effects and short RT of JDTic.
Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.
TLDR
The recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands, and their potential use as therapeutics are focused on.
Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists.
Receptor Occupancy of the k-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer
TLDR
Brain penetration and KOR target engagement after single oral doses (0.5–25 mg) of LY2456302 are investigated in 13 healthy human subjects and a dose of 10 mg appears well suited for further clinical testing.
Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050
TLDR
Brain penetration and KOR target engagement after single oral doses (0.5–25 mg) of LY2456302 are investigated in 13 healthy human subjects and a dose of 10 mg appears well suited for further clinical testing.
A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models.
TLDR
It is demonstrated for the first time that blockade of NOP receptors attenuates ethanol self-administration and ethanol-motivated behaviors, stress-induced ethanol seeking, andanol-induced stimulation of brain reward pathways in lines of rats that exhibit excessive ethanol consumption.
Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.
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