title: Pharmacophore Model To Discover OX1 and OX2 Orexin Receptor Ligands.
abstract: Small molecule agonists and antagonists of the orexinergic system have key implications for research and therapeutic purposes. We report a pharmacophore model trained on ∼200 antagonists and prospectively validated by screening a collection of ∼137,000 compounds. The resulting hit list, 395 compounds, was tested for OX1 and OX2 receptor activity using calcium mobilization assay in recombinant cell lines. Validation was conducted using both calcium mobilization and [(125)I]-orexin-A competition binding. Compounds 4-7 have weak agonist activity and Ki's in the 1-30 μM range; compounds 8-14 are antagonists with Ki's in the 0.1-10 μM range for OX2 and 1-50 μM for the OX1 receptor. Docking simulations were used to devise a working hypothesis where two subpockets are important for activation, one between TM5 and TM6 lined by Phe5.42, Tyr5.47, and Tyr6.48 and another above the orthosteric pocket lined by Asp2.65 and Tyr7.32.
authors.affiliation: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , P.O. Box 56, FIN-00014 Helsinki, Finland.|Faculty of Veterinary Medicine, Department of Veterinary Biosciences, University of Helsinki , P.O. Box 66, FIN-00014 Helsinki, Finland.
authors.forename: Ainoleena
authors.initials: A
authors.lastname: Turku
authors.affiliation: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , P.O. Box 56, FIN-00014 Helsinki, Finland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Borrel
authors.affiliation: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , P.O. Box 56, FIN-00014 Helsinki, Finland.
authors.forename: Teppo O
authors.initials: TO
authors.lastname: Leino
authors.affiliation: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , P.O. Box 56, FIN-00014 Helsinki, Finland.
authors.forename: Lasse
authors.initials: L
authors.lastname: Karhu
authors.affiliation: Faculty of Veterinary Medicine, Department of Veterinary Biosciences, University of Helsinki , P.O. Box 66, FIN-00014 Helsinki, Finland.
authors.forename: Jyrki P
authors.initials: JP
authors.lastname: Kukkonen
authors.affiliation: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , P.O. Box 56, FIN-00014 Helsinki, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Xhaard
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D000068796:Orexin Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D064446:Orexin Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D008024:Ligands; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D002118:Calcium