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Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.

Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, Hart JC, Need AB, McKinzie JH, Statnick MA, Suico JG, McKinzie DL, Tauscher-Wisniewski S, Mitch CH, Stoltz RR, Wong CJ - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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Dose-dependent in vivo receptor occupancy at putative mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) by naloxone and LY2456302 60 minutes after administration. a, Naloxone showed dose- and concentration-dependent occupancy of putative opioid receptors in a manner consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg). The doses at which 50% of receptors were occupied (ED50) at MOR, KOR, and DOR were 0.49, 0.75, and 3.45mg/kg, respectively. b, LY2456302 saturated putative KOR at all doses tested (3–300mg/kg). At higher doses, putative MOR and DOR occupancies were observed (ED50 values = 84.4 and 214.6mg/kg, respectively). LY2456302 selectively occupies KOR in the rat at doses <100mg/kg PO. Some engagement of MOR and DOR is evident at 100 and 300mg/kg (corresponding to brain exposures >473ng/g; see supplemental Table S1). Chemical structures of naloxone and LY2456302 are shown in insets.
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Figure 1: Dose-dependent in vivo receptor occupancy at putative mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) by naloxone and LY2456302 60 minutes after administration. a, Naloxone showed dose- and concentration-dependent occupancy of putative opioid receptors in a manner consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg). The doses at which 50% of receptors were occupied (ED50) at MOR, KOR, and DOR were 0.49, 0.75, and 3.45mg/kg, respectively. b, LY2456302 saturated putative KOR at all doses tested (3–300mg/kg). At higher doses, putative MOR and DOR occupancies were observed (ED50 values = 84.4 and 214.6mg/kg, respectively). LY2456302 selectively occupies KOR in the rat at doses <100mg/kg PO. Some engagement of MOR and DOR is evident at 100 and 300mg/kg (corresponding to brain exposures >473ng/g; see supplemental Table S1). Chemical structures of naloxone and LY2456302 are shown in insets.

Mentions: LY2456302 ((S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; chemical structure shown in Figure 1b inset) is a structurally novel, selective KOR antagonist with good central penetration and in vivo receptor occupancy that demonstrates efficacy in a number of preclinical models (Rorick-Kehn et al., 2014). In single- and multiple-dose clinical studies, LY2456302 was well tolerated up to doses of 35mg (Lowe et al., 2014). In a single-dose positron emission tomography study, LY2456302 demonstrated excellent central penetration and potent receptor occupancy in healthy human subjects, with full KOR occupancy at the 10-mg dose (Tauscher et al., 2012). Because MOR antagonist activity may be observed at higher doses of LY2456302, the current study was designed to identify the dose at which LY2456302 produces MOR antagonism in healthy subjects, thus confirming that lower doses remain selective for KORs.


Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.

Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, Hart JC, Need AB, McKinzie JH, Statnick MA, Suico JG, McKinzie DL, Tauscher-Wisniewski S, Mitch CH, Stoltz RR, Wong CJ - Int. J. Neuropsychopharmacol. (2014)

Dose-dependent in vivo receptor occupancy at putative mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) by naloxone and LY2456302 60 minutes after administration. a, Naloxone showed dose- and concentration-dependent occupancy of putative opioid receptors in a manner consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg). The doses at which 50% of receptors were occupied (ED50) at MOR, KOR, and DOR were 0.49, 0.75, and 3.45mg/kg, respectively. b, LY2456302 saturated putative KOR at all doses tested (3–300mg/kg). At higher doses, putative MOR and DOR occupancies were observed (ED50 values = 84.4 and 214.6mg/kg, respectively). LY2456302 selectively occupies KOR in the rat at doses <100mg/kg PO. Some engagement of MOR and DOR is evident at 100 and 300mg/kg (corresponding to brain exposures >473ng/g; see supplemental Table S1). Chemical structures of naloxone and LY2456302 are shown in insets.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4368892&req=5

Figure 1: Dose-dependent in vivo receptor occupancy at putative mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) by naloxone and LY2456302 60 minutes after administration. a, Naloxone showed dose- and concentration-dependent occupancy of putative opioid receptors in a manner consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg). The doses at which 50% of receptors were occupied (ED50) at MOR, KOR, and DOR were 0.49, 0.75, and 3.45mg/kg, respectively. b, LY2456302 saturated putative KOR at all doses tested (3–300mg/kg). At higher doses, putative MOR and DOR occupancies were observed (ED50 values = 84.4 and 214.6mg/kg, respectively). LY2456302 selectively occupies KOR in the rat at doses <100mg/kg PO. Some engagement of MOR and DOR is evident at 100 and 300mg/kg (corresponding to brain exposures >473ng/g; see supplemental Table S1). Chemical structures of naloxone and LY2456302 are shown in insets.
Mentions: LY2456302 ((S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; chemical structure shown in Figure 1b inset) is a structurally novel, selective KOR antagonist with good central penetration and in vivo receptor occupancy that demonstrates efficacy in a number of preclinical models (Rorick-Kehn et al., 2014). In single- and multiple-dose clinical studies, LY2456302 was well tolerated up to doses of 35mg (Lowe et al., 2014). In a single-dose positron emission tomography study, LY2456302 demonstrated excellent central penetration and potent receptor occupancy in healthy human subjects, with full KOR occupancy at the 10-mg dose (Tauscher et al., 2012). Because MOR antagonist activity may be observed at higher doses of LY2456302, the current study was designed to identify the dose at which LY2456302 produces MOR antagonism in healthy subjects, thus confirming that lower doses remain selective for KORs.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus