Synthesis and Evaluation of Potentially Transdermal Morphine Derivatives

Abstract

Three new morphine-based compounds bearing arginyl moieties, compounds 7, 9a, and 9b, have been synthesized using solid phase and solution phase techniques with the aim of obtaining new transdermal analgesics. Preliminary biological assays have shown that these compounds have a relatively high affinity for opioid receptors, achieving ≥94 % inhibition of radioligand binding at a concentration of 10 µM in non-selective opioid binding assays. Further testing on two of the analogues, 9a and 9b, demonstrated that these compounds were acting as agonists, rather than antagonists, at the opioid receptors and 9b achieved the significant result of 73 % inhibition of contractile responses in the electrically stimulated guinea pig ileum assay at a concentration of 30 µM. Unfortunately, none of the molecules showed evidence of transdermal activity.