Analgesia
is commonly mediated through the mu or kappa opioid receptor agonism.
Unfortunately, selective mu or kappa receptor agonists often cause harmful side
effects. Recently, ligands exhibiting dual agonism to the opioid receptors,
such as to mu and kappa, or to mu and delta, have been suggested to temper
undesirable adverse effects while retaining analgesic activity. Herein we report
an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies
showed that some of these compounds have dual agonism on kappa and mu opioid
receptors, while some have triple agonism on kappa, mu, and delta. <i>In
vivo </i>studies on the lead dual kappa and mu opioid receptor agonist,
compound <b>10</b>, showed that it<b> </b>produced
analgesic activity while avoiding anxiogenic effects in murine models, thus
providing further strong evidence for the therapeutic advantages of dual opioid
receptor agonists over selective opioid receptor agonists.
The Role of Peripheral Opioid Receptors in the Development of Tolerance to Mu‐Opioid Receptor Agonists