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)
- 1 May 1986
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 29 (5) , 874-876
- https://doi.org/10.1021/jm00155a048
Abstract
In an effort to determine whether or not the basic nitrogens in the spacer of the bivalent ligand 6.beta.,6.beta.''-[ethylenebis(oxyethyleneiminol)]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.This publication has 2 references indexed in Scilit:
- Dimeric pentapeptide enkephalin: A novel probe of delta opiate receptorsLife Sciences, 1982
- Stereochemical studies on medicinal agents. 23. Synthesis and biological evaluation of 6-amino derivatives of naloxone and naltrexoneJournal of Medicinal Chemistry, 1977