The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor

Hempel, Christoph; Nörenberg, Wolfgang; Sobottka, Helga; Urban, Nicole; Nicke, Annette; Fischer, Wolfgang B.; Schaefer, Michael

doi:10.1016/j.neuropharm.2013.07.027

Cited by 34 publications

(33 citation statements)

References 51 publications

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“…Our data is in line with recent findings by Hempel et al, [29] who identified an inhibitory effect of phenothiazine class antipsychotics such as trifluoperazine as allosteric modulators of the human P2X7 receptor. Our calculated IC 50 value for TFP on human P2X7 is slightly higher at 6.4 vs 1.8 μM [29]. We also found that TFP had no inhibitory effect at rodent P2X7 receptors.…”

Section: Discussionsupporting

confidence: 93%

“…2). In our hands, the IC 50 value for inhibition of hP2X7-induced dye uptake by TFP was 6.4 μM (95 % confidence interval 5.6-7.3 μM, n=3 experiments) which is slightly higher than previously reported [29].…”

Section: Resultscontrasting

confidence: 64%

“…The related purinergic ion channel P2X4 is known to be blocked by several antidepressants with paroxetine, a selective serotonin reuptake inhibitor (SSRI), demonstrating the strongest inhibition [28]. The phenothiazine group of anti-psychotic agents including trifluoperazine have also recently been demonstrated to effectively block human P2X7 responses [29]; however, it is not known if P2X7 responses are inhibited by other antidepressant and mood stabilising compounds. Some antidepressants have been demonstrated to have anti-inflammatory effects in vitro although their mechanism of action is unknown [4,30].…”

Section: Introductionmentioning

confidence: 99%

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Paroxetine suppresses recombinant human P2X7 responses

Dao-Ung

Skarratt

Fuller

et al. 2015

Purinergic Signalling

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P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit antidepressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC 50 of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC 50 of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14+ monocytes was suppressed with trifluoperazine and paroxetine.

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Section: Discussionsupporting

confidence: 93%

Section: Resultscontrasting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Paroxetine suppresses recombinant human P2X7 responses

Dao-Ung

Skarratt

Fuller

et al. 2015

Purinergic Signalling

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“…A number of therapeutic drugs can also impair P2X7 activation. The antipsychotic drugs, prochlorperazine and trifluoperazine and to a lesser extent triflupromoazine can each impair human, but not rodent, P2X7 channel and pore activation (Hempel et al, 2013). Colchicine, a drug used to treat gout and familial Mediterranean fever, can inhibit P2X7 pore but not channel activation (Marques-da-Silva et al, 2011).…”

Section: Modulators Of P2x7 Receptor Activationmentioning

confidence: 99%

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

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“…Several lines of evidence point to an intracellular localization of the TIIAS binding site, as follows: 1) the delayed on-and offset of hP2X7 inhibition with extracellularly applied TIIAS, 2) the activity of intracellularly perfused TIIAS, and 3) the voltage dependence of the inhibition with regard to onset times and efficiency. An intracellular binding site would distinguish TIIAS from other gating and/or binding modifiers of hP2X7, such as clemastine or perazines, which presumably act via an extracellularly accessible point of attack (Nörenberg et al, 2011;Hempel et al, 2013), or ivermectin, which has been proposed to intercalate between transmembrane helices of P2X4 and possibly also human P2X7 (Silberberg et al, 2007;Nörenberg et al, 2012). Binding of TIIAS to the intracellular portion of the receptor may require positively charged amino acids to neutralize the negative charge of the drug.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone II A Sulfonate, but Not Tanshinone II A, Acts as Potent Negative Allosteric Modulator of the Human Purinergic Receptor P2X7

Kaiser

Sobottka

Fischer

et al. 2014

J Pharmacol Exp Ther

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Tanshinone II A sulfonate (TIIAS) was identified as a potent, selective blocker of purinergic receptor P2X7 in a compound library screen. In this study, a detailed characterization of the pharmacologic effects of TIIAS on P2X7 is provided. Because TIIAS is a derivative of tanshinone II A (TIIA) and both compounds have been used interchangeably, TIIA was included in some assays. Fluorometric and electrophysiologic assays were used to characterize effects of TIIAS and TIIA on recombinantly expressed human, rat, and mouse P2X7. Results were confirmed in human monocyte-derived macrophages expressing native P2X7. In all experiments, involvement of P2X7 was verified using established P2X7 antagonists. TIIAS, but not TIIA, reduces Ca 21 influx via human P2X7 (hP2X7) with an IC 50 of 4.3 mM. TIIAS was less potent at mouse P2X7 and poorly inhibited rat P2X7. Monitoring of YO-PRO-1 uptake confirmed these findings, indicating that formation of the hP2X7 pore is also suppressed by TIIAS. Electrophysiologic experiments revealed a noncompetitive mode of action. TIIAS time-dependently inhibits hP2X7 gating, possibly by binding to the intracellular domain of the receptor. Inhibition of native P2X7 in macrophages by TIIAS was confirmed by monitoring Ca 21 influx, YO-PRO-1 uptake, and release of the proinflammatory cytokine interleukin-1b. Fluorometric experiments involving recombinantly expressed rat P2X2 and human P2X4 were conducted and verified the compound's selectivity. Our data suggest that hP2X7 is a molecular target of TIIAS, but not of TIIA, a compound with different pharmacologic properties.

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The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor

Cited by 34 publications

References 51 publications

Paroxetine suppresses recombinant human P2X7 responses

Paroxetine suppresses recombinant human P2X7 responses

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

Tanshinone II A Sulfonate, but Not Tanshinone II A, Acts as Potent Negative Allosteric Modulator of the Human Purinergic Receptor P2X7

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