Prolonged and neuropathic pain affects 100 million Americans and costs the economy over 500 billion dollars annually. Current treatments are inadequate and there is an epidemic of deaths from the misuse of prescription drugs for pain, with tens of thousands dying annually. Clearly, more efficacious and safer drugs are needed. Based on insights from genomic, proteomic and mechanistic studies of prolonged and neuropathic pain in the central and peripheral nervous systems, we have suggested that the design and synthesis of multivalent ligands that address the disease states will provide unique opportunities to design ligands for prolonged and neuropathic pain. At the same time, these ligands will have greatly reduced or none of the toxicities of current opiate drugs including constipation, respiratory depression, development of addiction, dependence and tolerance. We will discuss the design, synthesis and biological evaluation of a number of peptidomimetic ligands that have agonist activities at mu and delta opioid receptors and antagonist activities at neurokinin-1 receptors with highly potent analgesic effects in acute and neuropathic pain, cross the blood brain barrier, do not develop tolerance, have no addiction potential and do not have the toxicities of current opioids.

Application of multivalent ligand design for the treatment of prolonged pain and addiction without toxicities

248th National Meeting (2014)

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