Chronic pain syndromes remain poorly managed due to inadequate efficacy of currently available drugs or undesirable side effects associated with doses or long-term administration needed to obtain pain relief. There remains a critical need for novel therapies to enhance the efficacy and the safety of treatments for chronic pain. In an effort to develop non-addictive analgesic drugs, novel multifunctional opioid peptides were designed, synthesized and evaluated for their biological activities in vitro and in vivo assays. Lead compounds were shown to possess new biological profile, MOR/DOR agonist and KOR antagonist (or partial agonist) activity, which can block KOR-induced adverse and addictive liabilities in chronic pain states while retaining potent antinociceptive effects of MOR/DOR agonist. (Figure) These ligands exhibited strong analgesic effects along with a high potential to penetrate the blood brain barrier in in vivo tests and high metabolic stability in human plasma. These ligands open up the possibility of developing novel opioid drugs with clear therapeutic advantages for the treatment of chronic pain by additional modulation of KOR activity, because increased KOR activation can be blocked by the KOR antagonist function.

Yeon Sun Lee is research associate professor at Department of Pharmacology, University of Arizona, Tucson and senior director (part-time) at Peptide Logic, Ltd. San Diego, California. Her research interests include peptide and peptidomimetic drug design, peptide structure-function relationship, topographical considerations in molecular recognition, organic, amino acid and peptide synthesis and pain mechanisms and drug abuse. Besides her academic career, she is a holder of several patents. More details 

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