High-affinity, non-peptide agonists for the ORL1 (orphanin FQ/nociceptin) receptor

The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phen yl-1,3,8-triazaspiro [4.5]decan-4-one, 1a, as a high-affinity ligand for th e human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a se ries of optimized Ligands. These compounds exhibit high affinity for the hu man ORL1 receptor, exhibit moderate to good selectivity versus opioid recep tors, and behave as full agonists in biochemical assays. In this paper we p resent the synthesis, structure-activity relationship (SAR), and biochemica l characterization of substituted 1-phenyl-1,3,8-triazaspiro [4.5]decan-4-o nes culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthal en-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, pot ent ORL1 receptor agonists with good to moderate selectivity versus the oth er opioid receptors.