title: Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line.
abstract: OBJECTIVE
  An influx drug/proton antiporter of unknown structure has been functionally demonstrated at the blood-brain barrier. This transporter, which handles some psychoactive drugs like diphenhydramine, clonidine, oxycodone, nicotine and cocaine, could represent a new pharmacological target in drug addiction therapy. However, at present there are no known drugs/inhibitors that effectively inhibit/modulate this transporter in vivo.
  
  
  METHODS
  The FLAPpharm approach was used to establish a pharmacophore model for inhibitors of this transporter. The inhibitory potency of 44 selected compounds was determined against the specific substrate, [(3)H]-clonidine, in the human cerebral endothelial cell line hCMEC/D3 and ranked as good, medium, weak or non-inhibitor.
  
  
  RESULTS
  The pharmacophore model obtained was used as a template to screen xenobiotic and endogenous compounds from databases [Specs, Recon2, Human Metabolome Database (HMDB), human intestinal transporter database], and hypothetical candidates were tested in vitro to determine their inhibitory capacity with [(3)H]-clonidine. According to the transporter database, 80% of the proton antiporter inhibitor candidates could inhibit P-glycoprotein/MDR1/ABCB1 and specificity is improved by reducing inhibitor size/shape and increasing water solubility. Virtual screening results using HMDB and Recon2 for endogenous compounds appropriately scored tryptamine as an inhibitor.
  
  
  CONCLUSIONS
  The pharmacophore model for the proton-antiporter inhibitors was a good predictor of known inhibitors and allowed us to identify new good inhibitors. This model marks a new step towards the discovery of this drug/proton antiporter and will be of great use for the discovery and design of potent inhibitors that could potentially help to assess and validate its pharmacological role in drug addiction in vivo.
authors.affiliation: INSERM U1144, Variabilité de réponse aux psychotropes, Paris, 75006, France.|UMR-S 1144, Université Paris Descartes, Paris, 75006, France.|UMR-S 1144, Université Paris Diderot, Paris, 75013, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Chapy
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, 06123, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Département de recherche biopharmaceutique, Technologie Servier, Orléans, 45000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vayer
authors.affiliation: Département de recherche biopharmaceutique, Technologie Servier, Orléans, 45000, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.affiliation: Laboratoire de Pharmacochimie, Université de Genève, Genève, CH-1211, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: INSERM U1144, Variabilité de réponse aux psychotropes, Paris, 75006, France.|UMR-S 1144, Université Paris Descartes, Paris, 75006, France.|UMR-S 1144, Université Paris Diderot, Paris, 75013, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: INSERM U1144, Variabilité de réponse aux psychotropes, Paris, 75006, France.|UMR-S 1144, Université Paris Descartes, Paris, 75006, France.|UMR-S 1144, Université Paris Diderot, Paris, 75013, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: INSERM U1144, Variabilité de réponse aux psychotropes, Paris, 75006, France.|UMR-S 1144, Université Paris Descartes, Paris, 75006, France.|UMR-S 1144, Université Paris Diderot, Paris, 75013, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, 06123, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D017920:Antiporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002460:Cell Line; D003000:Clonidine / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D009270:Naloxone / Q000494:pharmacology*; D011522:Protons; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017920:Antiporters; D011522:Protons; D011955:Receptors, Drug; D009270:Naloxone; D003042:Cocaine; D003000:Clonidine