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Opioid Antagonist Activity of Naltrexone-Derived Bivalent Ligands:  Importance of a Properly Oriented Molecular Scaffold To Guide “Address” Recognition at κ Opioid Receptors

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journal contribution
posted on 26.04.1996, 00:00 by MariaLaura Bolognesi, William H. Ojala, William B. Gleason, Jane F. Griffin, Francine Farouz-Grant, Dennis L. Larson, Akira E. Takemori, Philip S. Portoghese
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.