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 II 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 II 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 II agonism with efficacy at kappa and delta opioid receptors, the nociceptin opioid peptide (NOP) receptor, sigma 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.