title: Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists.
abstract: We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.
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: 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: 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: 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 agonist; NOP receptor agonist