IUPHAR Review - Bivalent and bifunctional opioid receptor ligands as novel analgesics

Though efficacious in managing chronic, severe pain, opioid analgesics are accompanied by significant adverse effects including constipation, tolerance, dependence, and respiratory depression. The life-threatening risks associated with µ opioid receptor agonist-based analgesics challenges their use...

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Bibliographic Details
Published in:Pharmacological research 2023-11, Vol.197, p.106966-106966, Article 106966
Main Authors: Rehrauer, Kyle J., Cunningham, Christopher W.
Format: Article
Language:English
Subjects:
Analgesics
Bifunctional ligand
Bivalent ligand
Drug design
Drug discovery
Opioid
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Summary:Though efficacious in managing chronic, severe pain, opioid analgesics are accompanied by significant adverse effects including constipation, tolerance, dependence, and respiratory depression. The life-threatening risks associated with µ opioid receptor agonist-based analgesics challenges their use in clinic. A rational approach to combatting these adverse effects is to develop agents that incorporate activity at a second pharmacologic target in addition to µ opioid receptor activation. The promise of such bivalent or bifunctional ligands is the development of an analgesic with an improved side effect profile. In this review, we highlight ongoing efforts in the development of bivalent and bifunctional analgesics that combine µ agonism with efficacy at κ and δ opioid receptors, the nociceptin opioid peptide (NOP) receptor, σ receptors, and cannabinoid receptors. Several examples of bifunctional analgesics in preclinical and clinical development are highlighted, as are strategies being employed toward the rational design of novel agents.
ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2023.106966