Opioid antagonist activity of naltrexone-derived bivalent ligands: Importance of a properly oriented molecular scaffold to guide "address" recognition at κ opioid receptors

The presence of a molecular scaffold to orient a basic group is important for potent and selective κ opioid antagonist selectivity. An attempt to determine how the geometry of the scaffold affects this selectivity has led to the synthesis of a bivalent ligand (5) whose linker constrains the N17′ basic nitrogen (the "address") to a position that is 6.5 Å from N17′ in the κ antagonist norBNI (1) when these molecules are superimposed. The fact that compound 5 was found to be a highly selective and potent μ-selective antagonist supports the idea that the position of N17′ in 5 precludes effective ion pairing with the nonconserved residue Glu297 on outer loop 3 of the κ opioid receptor. The high μ receptor binding affinity and in vitro pharmacological selectivity of 5 coupled with its presumed low central nervous system bioavailability suggest that it may be a useful antagonist for the investigation of peripheral μ opioid receptors.