Probes for narcotic receptor mediated phenomena. 7. Synthesis and pharmacological properties of irreversible ligands specific for .mu. or .delta. opiate receptors

Abstract

Syntheses of affinity reagents for opiate receptors based on the fentanyl, endo-ethenotetrahydrooripavine and etonitazene carbon-nitrogen skeletons are described. The isothiocyanate bromoacetamido and methylfumaramido alkylating functions were employed in these compounds, some of which were previously .mu. specific (12, [1-[2-(diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-isothiocyanatobenzimidazole], BIT) and .delta. specific (8) [N-[1-[2-(4-isothiocyanatophenyl)ethyl]-4-piperidinyl]-N-phenylpropanamide], FIT and 19 [7.alpha.-(methylfumaramido)-6, 14-endo-ethenotetrahydrooripavine], FAO) in vitro. Antinociceptive activity of the title compounds was determined in the mouse hot-plate test, which revealed that certain compounds in each class showed morphine-like activity. The binding EC50 [median effective concentration] values against [3H]Dalamid for opiate receptors in NG108-15 (.delta. receptors) and rat brain membranes (.mu. + .delta. receptors) are also reported. With this type of experiment, it was possible to independently measure the apparent affinity of the etonitazene congeners 12-14 [5-(bromoacetamido)-1-[2-(diethylamino)ethyl]-2-(4-ethoxybenzyl)benzimidazole (13) and 1-[2-(diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-(methylfumoramido)benzimidazole (14)] for the .mu. and .delta. receptors.