The most highly abused
prescription drugs are
opioids used for the treatment of
pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat
pain while limiting the misuse or diversion of
pain medications. In addition to abuse liability,
opioid use is associated with unwanted side effects that complicate
pain management, including
opioid-induced
emesis and
constipation. This has resulted in restricting long-term doses of
opioids and inadequate treatment of both acute and chronic debilitating
pain, demonstrating a compelling need for novel
analgesics. Recent reports indicate that adaptations in endogenous
substance P/
neurokinin-1 receptor (NK1) are induced by
chronic pain and sustained
opioid exposure, and these changes may contribute to processes responsible for
opioid abuse liability,
emesis, and
analgesic tolerance. Here, we describe a multifunctional mu-/delta-
opioid agonist/NK1 antagonist compound [
Tyr-d-Ala-Gly-Phe-Met-
Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no
opioid-related
emesis or
constipation. In rodent models of acute and
neuropathic pain, TY027 demonstrates
analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative
opioid designed to contest the pathology created by
chronic pain and sustained
opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than
morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and
chronic pain.