ORL1 receptor ligands: Structure–activity relationships of 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones

• Published in: Bioorganic & medicinal chemistry letters Vol. 10; no. 8; pp. 831 - 834
• Main Authors: Röver, Stephan, Wichmann, Jürgen, Jenck, François, Adam, Geo, Cesura, Andrea M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.04.2000
• Subjects: Biological and medical sciences; Cell Line; Humans; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptors, Opioid - metabolism; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Structure-Activity Relationship; Triazines - chemistry; Triazines - pharmacology; Agonist; Structure activity relation; Nitrogen heterocycle; Lactam; μ Opioid receptor; Bicyclic compound; Affinity; κ Opioid receptor; Selectivity; Chemical synthesis; Spiran; Cis stereoisomer
• ISSN: 0960-894X
• DOI: 10.1016/S0960-894X(00)00111-6

We have investigated 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o nes as ligands for the ORL1 receptor. These unsophisticated, achiral compounds show remarkable affinity for the ORL1 receptor. Optimizing for selectivity we show that the maximum of affinity and selectivity versus the other opioid receptors is achieved for 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o ne 2e and 8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one 2q. The identified compounds (2e, 2q) are more or less equipotent to the natural ligand itself, both in the binding assay and in the functional GTPgammaS assay.