High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor

• Published in: Journal of medicinal chemistry Vol. 43; no. 7; pp. 1329 - 1338
• Main Authors: Röver, Stephan, Adam, Geo, Cesura, Andrea M, Galley, Guido, Jenck, François, Monsma, Frederick J, Wichmann, Jürgen, Dautzenberg, Frank M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.04.2000; Amer Chemical Soc
• Subjects: Binding, Competitive; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Opioid - agonists; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; ENDOGENOUS LIGAND; ORL RECEPTOR; KAPPA-OPIOID RECEPTORS; PROTEIN-COUPLED RECEPTOR; TISSUE DISTRIBUTION; GENE FAMILY; MOLECULAR-CLONING; LONG-TERM POTENTIATION; CDNA CLONING; NOCICEPTIN/ORPHANIN FQ; Agonist; Nitrogen heterocycle; Opioid receptor; Lactam; Non peptide compound; Tricyclic compound; In vitro; Spiran; Biological fixation; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Acenaphthylene derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991129q

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.