title: Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects.
abstract: 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.
authors.affiliation: Department of Pharmacology (T.M.L.-M., S.W.B., D.P.S., K.E.H., P.D., C.R.C., F.P., T.W.V.), and Department of Chemistry (T.Y., P.N, S.D., V.J.H.), University of Arizona, Tucson, Arizona; and Center for Excellence in Neuroscience, University of New England, Biddeford, Maine (K.E.H., D.G., E.J.B., F.P., T.W.V.).
authors.forename: T M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.forename: S W
authors.initials: SW
authors.lastname: Brookshire
authors.forename: D P
authors.initials: DP
authors.lastname: Skinner
authors.forename: K E
authors.initials: KE
authors.lastname: Hanlon
authors.forename: D
authors.initials: D
authors.lastname: Giuvelis
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: P
authors.initials: P
authors.lastname: Davis
authors.forename: C R
authors.initials: CR
authors.lastname: Campos
authors.forename: P
authors.initials: P
authors.lastname: Nair
authors.forename: S
authors.initials: S
authors.lastname: Deekonda
authors.forename: E J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: F
authors.initials: F
authors.lastname: Porreca
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: T W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D005289:Ferrets; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects; D009270:Naloxone / Q000008:administration & dosage / Q000009:adverse effects; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism* / Q000502:physiology; D013127:Spinal Nerves / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D009270:Naloxone; D009020:Morphine