title: Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles]: highly selective small-molecule nociceptin/orphanin FQ receptor agonists.
abstract: Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited 3H-N/OFQ binding to the NOP receptor (K(i) = 0.49 nM) but was >1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTP gamma S binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Grenzacher Strasse 124, CH-4070 Basel, Switzerland. sabine.kolczewski@roche.com
authors.forename: Sabine
authors.initials: S
authors.lastname: Kolczewski
authors.forename: Geo
authors.initials: G
authors.lastname: Adam
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cesura
authors.forename: François
authors.initials: F
authors.lastname: Jenck
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Thomas
authors.initials: T
authors.lastname: Oberhauser
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Poli
authors.forename: Felix
authors.initials: F
authors.lastname: Rössler
authors.forename: Stephan
authors.initials: S
authors.lastname: Röver
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wichmann
authors.forename: Frank M
authors.initials: FM
authors.lastname: Dautzenberg
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C470756:1-(4-isopropylcyclohexyl)-5'-methyl-2'-phenylhexahydrospiro(piperidine-4,1'-pyrrolo(3,4-c)pyrrole); D011725:Pyridines; D011758:Pyrroles; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human