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
Introduction
Major depression, characterized by negative mood, reduced motivation, and sometimes anhedonia and decreased energy, affects nearly 5% of people worldwide each year. Current antidepressants work well for some patients, but ∼60% suffer from unresolved residual symptoms or inadequate treatment response (Thase et al., 2001). As a result, some patients may abuse or misuse alcohol or other drugs in an attempt to reduce their depressive symptoms, often termed “self-medication” (Bolton et al., 2009). A recent study estimated that 16% of depressed patients also have a diagnosable addiction disorder (Sher et al., 2008). Such comorbidity puts patients at greater risk. Comorbid substance use in depressed patients is associated with greater symptom severity, inadequate treatment response, poorer prognosis (including increased risk of suicide), and persistence of depressive symptoms (Thase et al., 2001, Blanco et al., 2012). Therefore, a tremendous need exists for pharmacotherapies effective in treating both depressive symptoms and alcohol dependence.
Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward and stress systems, and play a key role in modulating neurotransmission in these areas (Mansour et al., 1987, Mansour et al., 1994, Margolis et al., 2006). In preclinical models, stress produces a prodepressive phenotype that is believed to be associated with the activation of kappa opioid receptors and subsequent downstream signaling events (Pliakas et al., 2001, Newton et al., 2002, McLaughlin et al., 2003, Shirayama et al., 2004, Land et al., 2008). Consistent with this hypothesis, kappa receptor agonists produce anxiogenic- and prodepressive-like effects in animals and humans (Pfeiffer et al., 1986, Todtenkopf et al., 2004; but see also Harden et al., 2012), whereas kappa receptor antagonists reliably exhibit antidepressant-like effects in animal models predictive of efficacy in the domains of mood and affect (Mague et al., 2003, Land et al., 2009, Carr et al., 2010). Unfortunately, there have been no reports of selective kappa receptor antagonists administered in clinical populations.
Kappa-selective antagonists also reduce ethanol intake and reinstatement in a number of preclinical paradigms (Deehan et al., 2012, Walker and Koob, 2008). While nonselective opioid antagonists such as naltrexone, an FDA-approved medication for alcohol dependence, are efficacious in animal models of alcoholism, they do not produce reliable antidepressant- or anxiolytic-like effects in animals or humans, likely due to functional opposition between mu and kappa receptors (Margolis et al., 2003, Spanagel et al., 1992). Similarly, antidepressants are weakly and inconsistently effective at reducing alcohol consumption in depressed patients with comorbid addictive disorders (Kranzler et al., 2006, Pettinati et al., 2010). Because kappa antagonists demonstrate efficacy in animal models predictive of efficacy in mood and addictive disorders, they have the potential to treat depressed patients with comorbid alcohol dependence.
Molecules targeting specific biological mechanisms are powerful tools for elucidating biological function. Most current knowledge of the kappa opioid system comes from studies on the prototypical antagonists, norbinaltorphimine (nor-BNI) and (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 (JDTic), which have unusual pharmacokinetic properties, including delayed onset of centrally-mediated effects (24–48 h) and very long duration of pharmacodynamic effects (28+ days; Munro et al., 2012, Patkar et al., 2013), that complicate research design and interpretation of the results. Long-duration activity of an antagonist can result in biological consequences that are different from that of short-term receptor blockade; differential biochemical modifications occur at the receptor level and at down-stream targets as a result of prolonged gating of agonist from the receptor. In order to expand and crystallize our current understanding of the biological basis of kappa opioid receptor function, the purpose of the present experiments was two-fold: first, to pharmacologically characterize (S)-3-fluoro4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (LY2456302) as an improved research tool for studying the kappa opioid receptor system; and second, to examine its antidepressant-like effects and its ability to decrease ethanol consumption.
Section snippets
Drugs and reagents
(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (LY2456302; Diaz Buezo et al., 2009, Mitch et al., 2011), LY2048978, JDTic, and GR103545 were synthesized at Lilly Research Laboratories. Naltrexone HCl, DAMGO acetate, DPDPE hydrate, naltriben methanesulfonate hydrate, U-69593, morphine sulfate, imipramine HCl, chlordiazepoxide HCl, phencyclidine HCl, and formalin solution (10%, diluted to 5%) were purchased from Sigma Aldrich (St. Louis, MO). LY2456302,
In vitro receptor binding and functional activity
LY2456302 (Fig. 1) was tested in filtration radioligand binding and GTP-γ-35S functional assays using membranes prepared from HEK or CHO cells expressing cloned human mu-, kappa-, and delta-opioid receptor subtypes (Mitch et al., 2011). LY2456302 bound with high affinity to the human kappa opioid receptor with a 30-fold higher affinity over the human mu opioid receptor and 190-fold higher affinity over the human delta opioid receptor (Table 1; Mitch et al., 2011). By comparison, naltrexone had
Discussion
LY2456302 is a structurally-unique, high-affinity, selective antagonist at the kappa opioid receptor (Diaz Buezo et al., 2009, Mitch et al., 2011), with approximately 30- and 200-fold selectivity over mu and delta opioid receptors, respectively, as assessed in in vitro binding and functional assays. LY2456302 had no appreciable affinity at several non-opioid cell surface receptor targets, including monoaminergic, muscarinic, cholinergic, and adrenergic receptors, as well as the central
Funding/conflict of interest
Financial support for the research provided by Eli Lilly and Company. All authors were employees of, and stockholders in, Eli Lilly and Company at the time the experiments were conducted.
Authorship contributions
Participated in research design: Rorick-Kehn, Statnick, Witkin, Kahl, Cramer, Mitch, D McKinzie, Forster.
Conducted experiments: Rorick-Kehn, Crile, Shaw, Sahr, J McKinzie, Eberle, Adams, Li, Kahl, D McKinzie, Forster.
Contributed new reagents or analytic tools: Quimby, Diaz, Jimenez, Pedregal, Mitch, Anderson, D McKinzie.
Performed data analysis: Rorick-Kehn, Crile, Shaw, Sahr, J McKinzie, Eberle, Adams, Li, Kahl, Anderson, Cramer, D McKinzie, Witkin, Forster.
Wrote or contributed to the writing
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