Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human

Rorick-Kehn, Linda; Witcher, Jennifer; Lowe, Stephen L.; Gonzales, Celedon; Weller, Mary A.; Bell, Robert L.; Hart, John C.; Need, Anne B.; McKinzie, Jamie H.; Statnick, Michael A.; Suico, Jeffrey G.; McKinzie, David L.; Tauscher-Wisniewski, Sitra; Mitch, Charles H.; Stoltz, Randall; Wong, Conrad J.

doi:10.1093/ijnp/pyu036

Cited by 32 publications

(26 citation statements)

References 29 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Attenuation of the μ-opioid agonist activity of buprenorphine by samidorphan was shown by the pupillometry data, a physiological measure for studying the centrally mediated effects of opioids. 22 In the present study, BUP/SAM showed lower pupil constriction compared with that induced by buprenorphine alone, providing objective validation of the observed subjective outcomes.…”

Section: Discussionsupporting

confidence: 76%

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial

Pathak

Vince

Kelsh

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a μ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2 mg/2 mg), at 4-fold (8 mg/8 mg) and 8-fold (16 mg/16 mg) the therapeutic dose, and buprenorphine alone (8 mg and 16 mg). The primary end point was maximum effect (E ) on the visual analog scale for "at the moment" Drug Liking. E of Drug Liking for the BUP/SAM 2 mg/2 mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking E compared to placebo. Drug Liking E for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

show abstract

Section: Discussionsupporting

confidence: 76%

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial

Pathak

Vince

Kelsh

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…In our selectivity experiments, we also saw modest blockade of our DAMGO induced effects at just 10 nM JNJ-67953964. While some MOR antagonism has been reported for this compound previously [25,40], we were surprised to detect it at this concentration, which did not achieve full KOR blockade in this preparation. Together, these observations indicate potentially important, unanticipated properties of JNJ-67953964.…”

Section: Discussioncontrasting

confidence: 55%

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Margolis

Wallace

Orden

et al. 2020

Preprint

View full text Add to dashboard Cite

19Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of 20 stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR 21 agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to 22 aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic 23 approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain 24 slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, 25 BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently 26 reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and 27 BTRX-395750 fully blocked U-69,593 currents (IC 50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively).28 JNJ-67953964 showed an IC 50 of 0.3 ± 1.3 nM. PF-04455242 (IC 50 = 19.6 ± 16 nM) exhibited 29 partial antagonist activity (~60% maximal blockade). In 50% of neurons, 1 M PF-04455242 30 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not 31 affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO 32 or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked 33 DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) 34 rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we 35 show electrophysiological evidence of key differences amongst KOR antagonists that could 36 impact their therapeutic potential and have not been observed using recombinant systems. The 37 results of this study demonstrate the value of characterizing compounds in native neuronal tissue 38 and within disorder-relevant circuits implicated in neurobehavioral disorders. Introduction 40One of the major challenges in drug development is predicting whole animal responses 42 indicate that the effect of drugs on G protein coupled receptor function in situ in brain tissue is not 43 reliably predicted from results in expression systems [3][4][5][6][7][8]. Therefore pharmacological 44 characterizations made in brain tissue likely relate better to behavioral outcomes than those made 45 in cell-based expression assays. 46Interest in the kappa opioid receptor (KOR) as a target for therapeutic development has 47 been growing consistently as clinical and preclinical studies have identified its role in aversive 48 behavioral states. KOR agonists produce profound adverse effects in humans, specifically 49 fatigue, sedation, confusion, impaired concentration, and anxiety. Furthermore at higher 50 concentrations visual and auditory hallucinations and feelings of depersonalization have been 51 reported [9,10]. Homologous effects have been described in animal models (reviewed in [11]). 52 Finally, blockade or genetic deletion of the KOR significantly reduces aversive responses to stress 53 [12-14], drug withdrawal [15-17], and pain [18], and has antidepres...

show abstract

“…It was previously shown that LY2456302 had a 30-fold selectivity over MOR and DOR (Rorick-Kehn et al, 2014). To further assess any MOR activity, LY2456302 (4-60 mg) was orally administered to healthy humans to assess the effect on fentanyl-induced miosis in a previous pupillometry study (Rorick-Kehn et al, 2015). Doses of 25-60 mg yielded minimal to moderate MOR blockade, with no effect seen at 4 and 10 mg.…”

Section: Discussionmentioning

confidence: 99%

Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

Naganawa

Dickinson

Zheng

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The k-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer 11 C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (r max ) and IC 50 . LY2456302 dose dependently blocked the binding of 11 C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the r max and IC 50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that r max is 100%, IC 50 was estimated as 0.83 ng/ml.

show abstract

Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human

Cited by 32 publications

References 29 publications

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

Contact Info

Product

Resources

About