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 import ant for potent and selective kappa opioid antagonist selectivity. An a ttempt to determine how the geometry of the scaffold affects this sele ctivity has led to the synthesis of a bivalent ligand (5) whose linker constrains the N17' basic nitrogen (the ''address'') to a position th at is 6.5 Angstrom from N17' in the kappa antagonist norBNI (1) when t hese 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 w ith the nonconserved residue Glu297 on outer loop 3 of the kappa opioi d receptor. The high mu receptor binding affinity and in vitro pharmac ological selectivity of 5 coupled with its presumed low central nervou s system bioavailability suggest that it may be a useful antagonist fo r the investigation of peripheral mu opioid receptors.