Strong opioid analgesics, including
morphine, are the mainstays
for treating moderate to severe acute pain and alleviating chronic
cancer pain. However, opioid-related adverse effects, including nausea
or vomiting, sedation, respiratory depression, constipation, pruritus
(itch), analgesic tolerance, and addiction and abuse liability, are
problematic. In addition, the use of opioids to relieve chronic noncancer
pain is controversial due to the “opioid crisis” characterized
by opioid misuse or abuse and escalating unintentional death rates
due to respiratory depression. Hence, considerable research internationally
has been aimed at the “Holy Grail” of the opioid analgesic
field, namely the discovery of novel and safer opioid analgesics with
improved opioid-related adverse effects. In this Perspective, medicinal
chemistry strategies are addressed, where structurally diverse nonmorphinan-based
opioid ligands derived from natural sources were deployed as lead
molecules. The current state of play, clinical or experimental status,
and novel opioid ligand discovery approaches are elaborated in the
context of retaining analgesia with improved safety and reduced adverse
effects, especially addiction liability.
The global “opioid crisis” has placed enormous
pressure
on the opioid ligand discovery community to produce novel opioid analgesics
with superior opioid-related adverse-effect profiles compared with
morphine. In this Perspective, the multitargeted opioid ligand strategy
for the discovery of opioid analgesics with superior preclinical therapeutic
indices relative to morphine is reviewed and discussed. Dual-targeted
μ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of
the MOP agonist activity, and are devoid of DOP or κ-opioid
(KOP) agonist activity, are sufficiently promising candidates to warrant
further investigation. Dual-targeted MOP/NOP partial agonists have
superior preclinical therapeutic indices to morphine and/or fentanyl
in nonhuman primates and are also considered promising. Based on the
poor preclinical and clinical therapeutic indices of cebranopadol,
which is a full agonist at MOP, DOP, and NOP receptors and a partial
agonist at the KOP receptor, this pharmacologic template should be
avoided.
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