title: Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198).
abstract: The nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely expressed GPCR involved in the modulation of pain, anxiety, and motor behaviors. Dissecting the functional properties of this receptor is limited by the lack of systemically active ligands that are brain permeant. The small molecule NOP receptor-selective, full agonist 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198) hydrochloride is an active, brain penetrant ligand, but its difficult and cost-prohibitive synthesis limits its widespread use and availability for animal studies. Here, we detail a more efficient and convenient method of synthesis, and use both in vitro and in vivo pharmacological assays to fully characterize this ligand. Specifically, we characterize the pharmacodynamics of Ro 64-6198 in cAMP and G-protein coupling in vitro and examine, for the first time, the effects of nociceptin/orphanin FQ and Ro 64-6198 in arrestin recruitment assays. Further, we examine the effects of Ro 64-6198 on analgesia, anxiety, and locomotor responses in vivo. This new synthesis and pharmacological characterization provide additional insights into the useful, systemically active, NOP receptor agonist Ro 64-6198.
authors.affiliation: Department of Anesthesiology, Basic Research Division, and Department of Anatomy and Neurobiology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chang
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Brieaddy
authors.affiliation: Department of Anesthesiology, Basic Research Division, and Department of Anatomy and Neurobiology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Harvey
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Anita H
authors.initials: AH
authors.lastname: Lewin
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Seltzman
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: P Anantha
authors.initials: PA
authors.lastname: Reddy
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McElhinny
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Desong
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Department of Anesthesiology, Basic Research Division, and Department of Anatomy and Neurobiology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Elisha E
authors.initials: EE
authors.lastname: Peterson
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.affiliation: Department of Anesthesiology, Basic Research Division, and Department of Anatomy and Neurobiology, Washington University Pain Center, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bruchas
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004735:Energy Transfer; D005106:Exploratory Behavior / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D010147:Pain Measurement / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D045442:Rotarod Performance Test; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: D007093:Imidazoles; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; D000242:Cyclic AMP; D002118:Calcium; D000094942:Nociceptin Receptor
keywords: GPCR; Ro 64-6198; arrestin; cAMP; locomotor activity; nociceptin/orphanin FQ opioid peptide receptor