title: High-affinity, non-peptide agonists for the ORL1 (orphanin FQ/nociceptin) receptor.
abstract: The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure-activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.
authors.affiliation: Pharma Division, Preclinical Research, Nervous System, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. stephan.roever@roche.com
authors.forename: S
authors.initials: S
authors.lastname: Röver
authors.forename: G
authors.initials: G
authors.lastname: Adam
authors.forename: A M
authors.initials: AM
authors.lastname: Cesura
authors.forename: G
authors.initials: G
authors.lastname: Galley
authors.forename: F
authors.initials: F
authors.lastname: Jenck
authors.forename: F J
authors.initials: FJ
authors.lastname: Monsma
authors.forename: J
authors.initials: J
authors.lastname: Wichmann
authors.forename: F M
authors.initials: FM
authors.lastname: Dautzenberg
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C461187:8-(5-methyl-1,2,3,4-tetrahydronapthalen-1-yl)-1,3,8-triazaspiro(4,5)decan-4-one; C121726:8-acenaphthen-1-yl-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one; D007093:Imidazoles; D008024:Ligands; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human