SYNTHESIS AND BIOLOGICAL-ACTIVITY OF THE PHOSPHATE AND SULFATE ESTERS OF NALOXONE AND NALTREXONE

Prodrugs of the two opiate antagonists naloxone and naltrexone, in particular the 3-monophosphate, 3-triphosphate, 9-monosulfate and 3,l4-disulfate eaters, have been synthesized and evaluated for: i) their ability to bind opioid receptors in vitro; and ii) their stability in both space and time upon entrapment into ex vivo human red blood cells (RBC). We find that, unlike the other esters, the mono- and triphosphate eaters of naloxone and naltrexone retain high (in the nmol range) affinities especially for mu- and kappa-opioid receptors. Owing to their hydrophilic nature, the two esters could possibly help in certain types of pharmacological experiments. Moreover, upon entrapment into human RBC, the triphosphate esters of naloxone and naltrexone display considerable ex vivo intracellular stability.