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

Neuropharmacology. 2014 Feb;77:131-44. doi: 10.1016/j.neuropharm.2013.09.021. Epub 2013 Sep 23.


Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.

Keywords: (2R,11R)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-[[(R)-tetrahydrofuran-2-yl]methyl]-2α,6α-methano-3-benzazocin-8-ol; (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide; 4-{4-[(pentylamino)methyl]phenoxy}benzamide; Addiction; Alcohol dependence; Antidepressant; CREB; DAMGO; DPDPE; Dynorphin; ERK; GR103545; JDTic; Kappa opioid antagonist; LY2048978; LY2456302; MAP kinase; MR2034; N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4,5]dec-8-yl]acetamide; Opioid receptors; PPI; U-69593; [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide]; [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin; [d-Pen(2),d-Pen(5)]-enkephalin; cyclic adenosine monophosphate-response element binding protein; extracellular regulated kinase; methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate; mitogen-activated protein kinase; prepulse inhibition.

MeSH terms

  • Analgesia
  • Animals
  • Antidepressive Agents / pharmacokinetics
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Depression / drug therapy*
  • Disease Models, Animal
  • Ethanol / administration & dosage
  • Male
  • Mice
  • Narcotic Antagonists / pharmacokinetics
  • Narcotic Antagonists / pharmacology*
  • Narcotic Antagonists / therapeutic use
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / therapeutic use
  • Rats
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Reflex, Startle / drug effects*
  • Self Administration
  • Sensory Gating / drug effects*


  • Antidepressive Agents
  • Benzamides
  • Narcotic Antagonists
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Ethanol
  • Aticaprant