title: Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol.
abstract: In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schunk
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Linz
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hinze
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Frormann
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oberbörsch
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Sundermann
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Zemolka
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Englberger
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Tieno
authors.initials: T
authors.lastname: Germann
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Babette-Y
authors.initials: BY
authors.lastname: Kögel
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schröder
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harlfinger
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Derek
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kless
authors.affiliation: ASCA GmbH Angewandte Synthesechemie Adlershof , Magnusstr. 11, 12489 Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Schick
authors.affiliation: ASCA GmbH Angewandte Synthesechemie Adlershof , Magnusstr. 11, 12489 Berlin, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Sonnenschein
keywords: MOP receptor agonists; NOP receptor agonists; analgesics; cebranopadol