Investigation of the Structural Requirements for the k-Selective Opioid Receptor Antagonist, 6β,6β';- [Ethylenebis (oxyethyleneimino)]bis[17- (cyclopropylmethyl) - 4,5a-epoxymorphinan-3,14-diol] (TENA)

In an effort to determine whether or not the basic nitrogens in the spacer of the bivalent ligand 6β6β';-[ethyl-enebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)-4,5a-epoxymorphinan-3,14-diol] (TENA, 1) is responsible for its selective K 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 K Opioid antagonist activity (IC₅₀ratio = 1) relative to TENA (IC₅₀ratio = 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 K Antagonist activity of TENA, the potent agonism associated with these monomers do not allow a firm conclusion in this regard.