Bivalent ligands are molecules which contain two pharmacophores, separated by a connecting chain (spanner). When the spanner is of sufficient length, the pharmacophores in such ligands have the potential for simultaneously occupying (bridging) proximal receptors. Because the constitution of the pharmacophore is not altered as the spanner length is changed, bivalent ligands are unique probes to explore organizational relationships between proximal recognition sites. Using this approach, we are employing several series of bivalent ligands to investigate different opioid receptor types. Such ligands are composed of opioid agonist or antagonist pharmacophore and glycine-containing spanners. Monovalent ligands, containing a chain similar to the spanner of the corresponding bivalent ligand series are used as reference compounds. The guinea pig ileum and mouse vas deferens preparations will be employed together with binding studies to delineate the relationship between spanner length and potency.
