Novel Hexahydrospiro[piperidine-4,1‘-pyrrolo[3,4-c]pyrroles]:  Highly Selective Small-Molecule Nociceptin/Orphanin FQ Receptor Agonists

• Published in: Journal of medicinal chemistry Vol. 46; no. 2; pp. 255 - 264
• Main Authors: Kolczewski, Sabine, Adam, Geo, Cesura, Andrea M, Jenck, François, Hennig, Michael, Oberhauser, Thomas, Poli, Sonia M, Rössler, Felix, Röver, Stephan, Wichmann, Jürgen, Dautzenberg, Frank M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16-01-2003
• Subjects: Binding, Competitive; Biological and medical sciences; Cell Line; Crystallography, X-Ray; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Radioligand Assay; Receptors, Opioid - agonists; Receptors, Opioid, delta - agonists; Receptors, Opioid, kappa - agonists; Receptors, Opioid, mu - agonists; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Human; Enantiomer(+); Agonist; Enantioselectivity; Nitrogen heterocycle; Non peptide compound; Selectivity; Tricyclic compound; In vitro; Spiran; Structure activity relation; N/OFQ receptor; Piperidine derivatives; Affinity; Chemical synthesis; Orphan receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0209174

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 GTPγS 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.