Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects

@article{Lowe2014SafetyTA,
  title={Safety, tolerability, and pharmacokinetic evaluation of single‐ and multiple‐ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects},
  author={Stephen Loucian Lowe and Conrad J. Wong and Jennifer Wright Witcher and Celedon R. Gonzales and Gemma L. Dickinson and Robert L. Bell and Linda M. Rorick-Kehn and MaryAnn Weller and Randall R. Stoltz and Jane E Royalty and Sitra Tauscher‐Wisniewski},
  journal={The Journal of Clinical Pharmacology},
  year={2014},
  volume={54}
}
Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high‐affinity, selective kappa opioid antagonist that demonstrates >30‐fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2–60 mg), multiple oral… 
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CERC‐501 was well tolerated, but it did not significantly alter the latency to start smoking or the number of cigarettes smoked, and did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking.
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Receptor Occupancy of the k-Opioid Antagonist LY 2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11 CLY 2795050
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 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.
Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140).
TLDR
Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice and exhibited a broad selectivity over a panel of off-target proteins.
Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET
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Data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET following kappa opioid agonist administration.
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