Synthesis and Investigation of Mixed µ-Opioid and [delta]-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain

Several studies have suggested functional association between µ-opioid and [delta]-opioid receptors and showed that µ-activity could be modulated by [delta]-ligands. The general conclusion is that agonists for the [delta]-receptor can enhance the analgesic potency and efficacy of µ-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the µ-agonist fentanyl and the [delta]-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel µ-bivalent/[delta]-bivalent compounds that demonstrate both µ-opioid and [delta]-opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects.