Casein Kinase 1δ/ε Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior

Abstract

Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/ε (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1δ/ε inhibition in treating multiple indications in the clinic.

Enteric innervation combined with proteomics for the evaluation of the effects of chronic fluoride exposure on the duodenum of rats

“…Rab-10 interacts with Melatonin receptor type 1A (P49218) which likely mediates the circadian actions of melatonin. Another protein that was found to interact with the proteins identified in the present study was Casein kinase 1 epsilon (Q9JJ76), a Ser-Thr protein kinase that acts as a key regulator of the central clock in the suprachiasmatic nucleus 69 and that is also involved in circadian regulation of gene expression 70 . Interestingly, a circadian rhythm for F has been described in humans, with the highest plasma F concentration found around midday and the lowest one in late afternoon 71 .…”

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

“…We and others previously identified a role for Csnk1e in regulating the behavioral response to multiple abused substances, including ethanol (Perreau-Lenz et al ., 2012), opioids (Bryant et al ., 2012, Wager et al ., 2014), and psychostimulants (Bryant et al ., 2009a, Bryant et al ., 2012, Palmer et al ., 2005, Zhou et al ., 2010). Here, we extended the consequences of Csnk1e deletion to include enhanced opioid-induced locomotor activity and opioid reward (Fig.…”

“…Csnk1e codes for a gene from a family of serine/threonine-selective kinases that possess diverse molecular substrates and biological functions (Cheong & Virshup, 2011), including regulation of the Wnt signaling pathway and in development and function as a clock gene in regulating circadian rhythms which are known to influence behavioral responses to substances of abuse (Parekh et al ., 2015). Non-selective pharmacological inhibition of CSNK1E and its closely related delta isoform (CSNK1D) can affect behaviors induced by multiple abused substances, including ethanol (Perreau-Lenz et al ., 2012), psychostimulants (Bryant et al ., 2009a, Zhou et al ., 2010), and opioids (Wager et al ., 2014). A recent study used pharmacological inhibition of CSNK1D/E to demonstrate attenuation of reinstatement of self-administration of the mu opioid receptor agonist fentanyl (Wager et al ., 2014).…”

“…Non-selective pharmacological inhibition of CSNK1E and its closely related delta isoform (CSNK1D) can affect behaviors induced by multiple abused substances, including ethanol (Perreau-Lenz et al ., 2012), psychostimulants (Bryant et al ., 2009a, Zhou et al ., 2010), and opioids (Wager et al ., 2014). A recent study used pharmacological inhibition of CSNK1D/E to demonstrate attenuation of reinstatement of self-administration of the mu opioid receptor agonist fentanyl (Wager et al ., 2014). However, it is unclear whether pharmacological inhibition of CK-1 inhibits the acute rewarding/reinforcing properties of these drugs or if it has a selective role in disrupting stimulus-responsive neuronal adaptations underlying reinstatement.…”

Facts and myths of selective casein kinase 1ε einhibition

“…All the other reported compounds behave mainly as dual CK1δ /ε inhibitors (ICK1δ /ε). Representative examples of dual inhibitors are PF-670462 [40], PF-5006739 [41], IC261 (SU5607) [42], and a small library of thiazoles was reported by Bischof and coworkers [43].…”