title: The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor.
abstract: P2X7, an ATP-gated cation channel, is involved in immune cell activation, hyperalgesia and neuropathic pain. By regulating cytokine release in the brain, P2X7 has been linked to the pathophysiology of mood disorders and schizophrenia. We here assess the impact of 123 drugs that act in the central nervous system on human P2X7. Most prominently, the tricyclic antipsychotics prochlorperazine (PCP) and trifluoperazine (TFP) potently inhibited P2X7-mediated Ca2+ entry, dye permeation and ionic currents. In divalent cation-containing bath solutions or after prolonged incubation, ATP-evoked P2X7 currents were inhibited by 10 μM PCP. This effect was not related to dopamine receptor antagonism. Surprisingly, PCP co-applied with ATP enhanced inward currents in bath solutions with low divalent cation concentrations. Intracellular perfusion with PCP did not substitute for the extracellularly applied drug, indicating that its binding sites are accessible from the extracellular space. Since P2X7 current potentiation by PCP was voltage-dependent, at least one site may be located within the electrical field of the membrane. While the channel opening and closure kinetic was altered by PCP, the apparent affinity of ATP remained unchanged (potentiation) or changed slightly (inhibition). Measurements in human monocyte-derived macrophages confirmed the PCP-induced inhibition of ATP-evoked Ca2+ influx, Yo-Pro-1 permeability, and whole cell currents. Interestingly, neither heterologously expressed rat or mouse P2X7 nor native P2X7 in rat astrocyte cultures or in mouse bone marrow-derived macrophages were inhibited by perazines with a similar potency. We conclude that perazine-type neuroleptics are potent, but species-selective allosteric modulators of human but not murine P2X7 receptors.
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors: Christoph
authors: C
authors: Hempel
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors: Wolfgang
authors: W
authors: Nörenberg
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors: Helga
authors: H
authors: Sobottka
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors: Nicole
authors: N
authors: Urban
authors: Max-Planck-Institute for Experimental Medicine, Hermann Rein-Str. 3, 37075 Göttingen, Germany.
authors: Annette
authors: A
authors: Nicke
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors: Wolfgang
authors: W
authors: Fischer
authors: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, 04107 Leipzig, Germany. Electronic address: michael.schaefer@medizin.uni-leipzig.de.
authors: Michael
authors: M
authors: Schaefer
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001583:Benzoxazoles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010464:Perazine / Q000494:pharmacology; D011346:Prochlorperazine / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: C587048:5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro(3,2-e)-1,4-diazepin-2-one; D014150:Antipsychotic Agents; D001570:Benzodiazepinones; D001583:Benzoxazoles; D058920:Purinergic P2X Receptor Antagonists; D011806:Quinolinium Compounds; D058486:Receptors, Purinergic P2X7; C089813:YO-PRO 1; D014268:Trifluoperazine; D010464:Perazine; D000255:Adenosine Triphosphate; D002118:Calcium; D011346:Prochlorperazine
keywords: 2′(3′)-0-(4-benzolybenzoyl)adenosine-5′-triphosphate; 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one; 5-BDBD; ATP pharmacology; AZ10606120; Antipsychotic drugs; BzATP; CaM; DIC; HBS; HEPES-buffered solution; Ligand-gated cation channel; N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; N-[2-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide; PCP; Prochlorperazine; Purinergic signalling; TFP; Trifluoperazine; W-7; Yo-Pro-1 dye permeation; [Ca(2+)](i); calmodulin; divalent cations; hMDM; human monocyte-derived macrophages; intracellular free Ca(2+) concentration; prochlorperazine; trifluoperazine