title: Design and synthesis of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of GlyT1 inhibitors: achieving selectivity against the mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors.
abstract: A novel class of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. A novel, straightforward and efficient synthetic strategy for the assembly of the target molecules is also presented.
authors.affiliation: Discovery Biology, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.forename: Simona M
authors.initials: SM
authors.lastname: Ceccarelli
authors.forename: Synèse
authors.initials: S
authors.lastname: Jolidon
authors.forename: Eva A
authors.initials: EA
authors.lastname: Krafft
authors.forename: Anke
authors.initials: A
authors.lastname: Kurt
authors.forename: Axel
authors.initials: A
authors.lastname: Maier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.forename: Henri
authors.initials: H
authors.lastname: Stalder
authors.forename: Deborah
authors.initials: D
authors.lastname: Studer
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
mesh_terms: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D018847:Opioid Peptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D011957:Receptors, Opioid / Q000737:chemistry; D013237:Stereoisomerism; D014965:X-Rays; D000097629:Nociceptin
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; D018847:Opioid Peptides; D010455:Peptides; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D000097629:Nociceptin; C493268:SLC6A9 protein, human