Novel mu, delta, kappa agonists, potential for development of novel analgesic agents

Current opioid analgesics such as morphine are known to exert their specific pharmacological effects through the mu (Jl) opioid receptor. Although powerful and effective pain killers, opioid Jl-agonists have many undesirable side effects including analgesic tolerance, respiratory depression, constipation, and abuse liability, that limit their utilization for long-term treatment of severe pain without hospitalization. Thus, efforts to discover new modalities for control of pain by the discovery of novel opioid analgesics that have high selectivity for other, more recently discovered, opioid receptors [delta (0) and kappa (K) receptors], or that have unique biological activity profiles, are receiving increasingly urgent attention. In this chapter, we will briefly profile some of the most promising agonist leads in this area, including compounds with mixed activity at opioid 0 and Jl receptors and extremely high selectivity for opioid K receptors. Such compounds include 0 agonist-Jl agonists and Jl agonist-O antagonists that appear to have promise as ligands with unique biological activity profiles and may offer approaches to limit the development of tolerance. Because of page limitations, not all lead compounds will be covered, but we will provide selected examples of each class of promising lead compounds and provide the reader with the various structures that appear to be promising in the development of new modalities of bioactivity. There is still much to learn about the biological potential of these various classes of compounds, especially as very few of them have been used in human medicine in a controlled clinical setting. Nonetheless, it is hoped that this brief review will stimulate others to do a more detailed examination of the problem and lead to the development of new ligands for the opioid receptors.