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Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid μ receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid μ and δ receptors. Several studies indicate that δ receptor agonists as well as δ receptor antagonists can provide beneficial modulation to the pharmacological effects of μ agonists. For example, δ agonists can enhance the analgesic potency and efficacy of μ agonists, and δ antagonists can prevent or diminish the development of tolerance and physical dependence by μ agonists. On the basis of these observations, the development of new opioid ligands possessing mixed μ agonist/δ agonist profile and mixed μ agonist/δ antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of μ-δ interactions and recent developments in identification of ligands possessing mixed μ agonist/δ agonist and μ agonist/δ antagonist activities is provided in this report.