Prolonged receptor blockade by opioid receptor probes

Opioid receptor interactions of morphinan-type opioids derivatized at the C-6 carbon were investigated. The compounds, designed as probes for studying opioid receptors, were characterized with regard to affinity for the rat brain mu receptor by competition with tritium-labeled dihydromorphine ((3)H-DHM). All compounds were also screened for prolonged receptor blockade by preincubation of rat brain membranes with the compounds alone, followed by extensive washing, and incubation with (3)H-DHM. The apparent dissociation profiles of congeners with prolonged blockade were further studied in the presence and absence of physiological concentrations of salts. Under conditions that completely dissociate the parent opioids, naltrexone, naloxone, and oxymorphone, the derivative l-(N-fluoresceinyl naltrexone thiosemicarbazone (6-FNX) and the opioid-steroid hybrids naloxone estrone azine (N-EH) and androstene bisoxymorphone azine (O-AD-O) showed more persistent receptor blockade than the bivalent opioid naloxonazine (NAz). Neither chemical reactivity nor a bivalent opioid structure was found to be a prerequisite for prolonged receptor blockade.