title: Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.
abstract: BACKGROUND
  Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.
  
  
  METHODS
  Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.
  
  
  RESULTS
  In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg).
  
  
  CONCLUSIONS
  We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz). rorickkehnlm@lilly.com.
authors: Linda M
authors: LM
authors: Rorick-Kehn
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Jennifer W
authors: JW
authors: Witcher
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Stephen L
authors: SL
authors: Lowe
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Celedon R
authors: CR
authors: Gonzales
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Mary Ann
authors: MA
authors: Weller
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Robert L
authors: RL
authors: Bell
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: John C
authors: JC
authors: Hart
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Anne B
authors: AB
authors: Need
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Jamie H
authors: JH
authors: McKinzie
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Michael A
authors: MA
authors: Statnick
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Jeffrey G
authors: JG
authors: Suico
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: David L
authors: DL
authors: McKinzie
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Sitra
authors: S
authors: Tauscher-Wisniewski
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Charles H
authors: CH
authors: Mitch
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Randall R
authors: RR
authors: Stoltz
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).
authors: Conrad J
authors: CJ
authors: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001549:Benzamides / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005283:Fentanyl / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015877:Miosis / Q000139:chemically induced / Q000188:drug therapy; D009020:Morphine / Q000494:pharmacology; D015878:Mydriasis / Q000139:chemically induced / Q000188:drug therapy; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000097:blood / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects* / Q000502:physiology; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001549:Benzamides; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D009020:Morphine; C000590915:Aticaprant; D005283:Fentanyl
keywords: LY2456302; dynorphin; kappa opioid receptor; pupillometry; translational biomarker
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