Irreversible Blockage of Opioid Receptor Types by Ester Homologues of β-Funaltrexamine

A series of ester homologues 2-5 of the μ receptor nonequilibrium antagonist β-funaltrexamine (1, β-FNA) was synthesized. These ligands were of interest in our investigation of the relationship between the structure of the ester function and the ability to irreversibly block μ opioid receptors. While all of the ligands were potent reversible agonists in the Guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations, most appeared to behave as irreversible antagonists of morphine. The benzyl 5 and phenethyl 6 esters possessed irreversible μ antagonist potency that was of similar magnitude to that of β-FNA in the GPI. In the MVD, all esters appeared to irreversibly block the agonist effect of morphine, but none of the compounds irreversibly antagonized [D-Ala²,D-Leu⁵]enkephalin to a significant degree. [³H]Dihydromorphine displacement studies revealed no relationship between the affinity of the esters 1–6 and the irreversible blockage of μ receptors in the GPI or MVD. Possible reasons for the observed structure-activity relationship are discussed.