Opioid agonist and antagonist bivalent ligands - the relationship between spacer length and selectivity at multiple opioid receptors

Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at .mu., .kappa. and .delta. opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as .mu. agonists on the electrically sitmulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guniea pig brain membranes showed a qualitatively similar profile at .mu. receptors as a function of spacer length. Also, .delta. receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the .mu. receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a .kappa. receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective .kappa. antagonist in the series. While receptor binding roughly parallels that of .kappa. antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at .mu. opioid receptors. The possible significance of these results is discussed.