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

The presence of a molecular scaffold to orient a basic group is important for potent and selective kappa 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 Angstrom from N17' in the kappa antagonist norBNI (1) when these molecules are superimposed. The fact that compound 5 was found to be a highly selective and potent mu-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 kappa opioid receptor. The high mu 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 mu opioid receptors.