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

We have investigated 5-cycloalkyl-1-phenyl-1,3,8-triaza-spirol4.5ldecan-4-o nes as ligands for the ORL1 receptor. These unsophisticated, achiral compou nds show remarkable affinity for the ORL1 receptor. Optimizing for selectiv ity we show that the maximum of affinity and selectivity versus the other o pioid receptors is achieved for 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro-[4 .5] decan-4-one 2e and 8-(cis-4-isopropyl-cyclohexyl)-1-phenyl- 1,3,8 -tria za-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 GTP gamma S assay. (C) 2000 Elsevier Science Ltd. All ri ghts reserved.