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

Rorick-Kehn, Linda; Witkin, Jeffrey M.; Statnick, Michael A.; Eberle, Elizabeth L.; McKinzie, Jamie H.; Kahl, Steven D.; Forster, Beth M.; Wong, Conrad J.; Li, Xia; Crile, Robert S.; Shaw, David B.; Sahr, Allison E.; Adams, Benjamin L.; Quimby, Steven J.; Dı́az, Nuria; Jiménez, Alma; Pedregal, Concepciòn; Mitch, Charles H.; Knopp, Kelly L.; Anderson, Wesley; Cramer, Jeffrey W.; McKinzie, David L.

doi:10.1016/j.neuropharm.2013.09.021

Cited by 134 publications

(150 citation statements)

References 54 publications

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“…For determination of KOR specificity, we utilized the recently developed short-acting KOR antagonist LY2444296. LY2444296 is a close analog of the compound LY2456302, which has been investigated in the clinic (Lowe et al, 2014; Rorick-Kehn et al, 2014; Reed et al, 2017). Prolactin and rotarod effects of the compounds studied here were blocked by LY2444296 (Figures 3B and 4C-D).…”

Section: Discussionmentioning

confidence: 99%

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Dunn

Reed

Guariglia

et al. 2018

International Journal of Neuropsychopharmacology

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BackgroundThe kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).MethodsBPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.ResultsBPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.ConclusionsBPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Dunn

Reed

Guariglia

et al. 2018

International Journal of Neuropsychopharmacology

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“…KOP-r/dynorphin activation is associated with the negative reinforcement aspects of alcohol addictions. It has been found that selective blockade of KOP-r attenuates excessive drinking, stress or cue -induced alcohol-seeking in mice and rats [Walker and Koob, 2008;Sperling et al, 2010;Deehan et al, 2012;Schank et al, 2012;Funk et al, 2014;Rorick-Kehn et al, 2014;Anderson et al, 2016;Zhou et al, 2017a] (but also see Mitchell et al, 2005;Sirohi et al, 2016). In line with these pharmacological results, alcohol drinking is decreased in KOP-r knockout mice [Kovacs et al, 2005].…”

Section: Kappa Opioid Receptor (Kop-r) and Dynorphin Systemmentioning

confidence: 91%

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

Zhou

Kreek

2018

J Pharmacol Exp Ther

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Addiction to specific drugs (such as alcohol, psychostimulants and opioids) shares some common direct or downstream effects on the brain stress-responsive systems, including arginine vasopressin and its V1b receptors, dynorphin and the kappa opioid receptors, proopiomelanocortin/β-endorphin and the mu opioid receptors, and the endocannabinoids. Further study of these systems, through laboratory-based and translational research, could lead to the discovery of novel treatment targets and the early optimization of interventions (for example, combination) for the pharmacological therapy of alcoholism.

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“…Animal models have suggested that κ-opioid receptor antagonists decrease depressive and anxiety behaviors in preclinical trials; 106,107 similarly, LY2456302's efficacy in the treatment of both mood and addictive disorders has been suggested. 108 In addition, RAPID will include a dose-finding trial for ketamine, with intravenous doses ranging from 0.1 to 1 mg kg − 1 per day for 3 days, compared with the active comparator midazolam (ClinicalTrials.gov identifier: NCT01920555). Taking a nod from our oncology colleagues, psychiatrists must begin to refer their difficult cases of treatment resistance to clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

Papakostas

Ionescu

2015

Mol Psychiatry

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Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments--especially for treatment-resistant depression (TRD)--are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

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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

Cited by 134 publications

References 54 publications

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

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