PF-670462 - CAS 950912-80-8
Catalog number: B0084-272284
Category: Inhibitor
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PF-670462 is a potent and selective inhibitor of CK1ε in isolated enzyme preparations. It inhibits PER protein nuclear translocation causing phase shifts in circadian rhythms and attenuates methamphetamine-stimulated locomotion in vivo. It less effectively inhibits a wide variety of related or common kinases. It disrupts circadian rhythms in cells and animals and blocks the locomotor response to amphetamines in mice. It remains unclear whether one of the kinases has a predominant role in regulating the circadian clock.
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B0084-272284 25 mg $198 In stock
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PF-670462; PF 670462; PF670462;PF-670462 HCl; PF-670462 hydrochloride
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1.Endogenous casein kinase-1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension.
Li DP;Zhou JJ;Pan HL J Physiol. 2015 Oct 1;593(19):4439-52. doi: 10.1113/JP270831. Epub 2015 Aug 18.
KEY POINTS: ;Increased NMDA receptor activity and excitability of presympathetic neurons in the hypothalamus can increase sympathetic nerve discharges leading to hypertension. In this study, we determined how protein kinases and phosphatases are involved in regulating NMDA receptor activity and firing activity of presympathetic neurons in the hypothalamus in normotensive and hypertensive rats. We show that casein kinase-1 inhibition increases NMDA receptor activity and excitability of presympathetic neurons in the hypothalamus and augments sympathetic nerve discharges in normotensive, but not in hypertensive, rats. Our data indicate that casein kinase-1 tonically regulates NMDA receptor activity by interacting with casein kinase-2 and protein phosphatases in the hypothalamus and that imbalance of NMDA receptor phosphorylation can augment the excitability of hypothalamic presympathetic neurons and sympathetic nerve discharges in hypertension. These findings help us understand the neuronal mechanism of hypertension, and reducing the NMDA receptor phosphorylation level may be effective for treating neurogenic hypertension.;ABSTRACT: ;Increased N-methyl-d-aspartate receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus is involved in elevated sympathetic outflow in hypertension.
2.Rapid, computer vision-enabled murine screening system identifies neuropharmacological potential of two new mechanisms.
Roberds SL;Filippov I;Alexandrov V;Hanania T;Brunner D Front Neurosci. 2011 Sep 9;5:103. doi: 10.3389/fnins.2011.00103. eCollection 2011.
The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10's activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.
3.Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes.
Meng QJ;Maywood ES;Bechtold DA;Lu WQ;Li J;Gibbs JE;Dupré SM;Chesham JE;Rajamohan F;Knafels J;Sneed B;Zawadzke LE;Ohren JF;Walton KM;Wager TT;Hastings MH;Loudon AS Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5. doi: 10.1073/pnas.1005101107. Epub 2010 Aug 9.
Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins. In mammals, mutations in casein kinase 1 (CK1) epsilon or delta can alter the circadian period, but the particular functions of the WT isoforms within the pacemaker remain unclear. We selectively targeted WT CK1epsilon and CK1delta using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking. Moreover, CK1delta is the principal regulator of the clock period: pharmacological inhibition of CK1delta, but not CK1epsilon, significantly lengthened circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro. Period lengthening mediated by CK1delta inhibition was accompanied by nuclear retention of PER2 protein both in vitro and in vivo. Furthermore, phase mapping of the molecular clockwork in vitro showed that PF-670462 treatment lengthened the period in a phase-specific manner, selectively extending the duration of PER2-mediated transcriptional feedback. These findings suggested that CK1delta inhibition might be effective in increasing the amplitude and synchronization of disrupted circadian oscillators.
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CAS 950912-80-8 PF-670462

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