Synthesis and
Characterization of a Dual Kappa-Delta
Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior
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Abstract
3-Iodobenzoyl
naltrexamine (IBNtxA) is a potent analgesic belonging
to the pharmacologically diverse 6β-amidoepoxymorphinan group
of opioids. We present the synthesis and pharmacological evaluation
of five analogs of IBNtxA. The scaffold of IBNtxA was modified by
removing the 14-hydroxy group, incorporating a 7,8 double bond and
various N-17 alkyl substituents. The structural modifications resulted
in analogs with picomolar affinities for opioid receptors. The lead
compound (<b>MP1104</b>) was found to exhibit approximately
15-fold greater antinociceptive potency (ED<sub>50</sub> = 0.33 mg/kg)
compared with morphine, mediated through the activation of kappa-
and delta-opioid receptors. Despite its kappa agonism, this lead derivative
did not cause place aversion or preference in mice in a place-conditioning
assay, even at doses 3 times the analgesic ED<sub>50</sub>. However,
pretreatment with the lead compound prevented the reward behavior
associated with cocaine in a conditioned place preference assay. Together,
these results suggest the promise of dual acting kappa- and delta-opioid
receptor agonists as analgesics and treatments for cocaine addiction