Investigation of the structural requirements for the .kappa.-selective opioid receptor antagonist 6.beta.,6.beta.'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)-4,5.alpha.-epoxymorphinan-3,14-diol](TENA)

In an effort to determine whether or not the basic nitrogens in the spacer of the bivalent ligand 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)4,5 alpha-epoxymorphinan-3,14-diol] (TENA, 1) is responsible for its selective kappa opioid antagonist activity, we have synthesized monovalent analogues 2-4 that contain a C-6 side chain with basic nitrogens. Analogue 2 behaved as a potent opioid agonist in the guinea pig ileum preparation (GPI) and possessed no significant kappa opioid antagonist activity (IC50 ratio = 1) relative to TENA (IC50 ratio = 20). The agonist activity of 3 and 4 interfered with the opioid antagonist assay and therefore did not permit evaluation of antagonist activity in a concentration range where TENA is effective. Although the results obtained with 2 are consistent with the requirement of a second opiate pharmacophore (rather than a second basic nitrogen in the spacer) for the kappa antagonist activity of TENA, the potent agonism associated with these monomers do not allow a firm conclusion in this regard.