Because of the serious side effects associated with mu-opioids such as morphine there is considerable interest in developing ligands for other opioid receptor types as potential therapeutic agents. Kappa opioid receptors are present in human brain and spinal cord in high concentrations, and there is considerable interest in developing kappa-selective compounds as potential neuroprotective and anticonvulsant agents as well as potential analgesic agents. Kappa agonists also potentially could be useful as immunomodulating agents in the treatment of HIV-associate encephalopathy. Therefore a better understanding of how these receptors function at a molecular level and how their endogenous ligands interact with them could be very important in the development of new therapeutic agents. The long term objectives of this project are to better understand the interactions of opioid peptides with kappa opioid receptors at a molecular level and to develop potent and selective peptide analogues as ligand for these receptors. This proposal focuses on the exploration of the structure-and conformation-activity relationships for antagonist vs. agonist activity, with the goal of identifying derivatives with antagonist activity at kappa receptors. Modifications chosen to impart antagonist activity will focus on the N-terminal region of the peptide. The central hypothesis of this research is that basic and aromatic groups are the key functionalities for interaction with kappa receptors, but that it is possible to incorporate these pharmacophoric groups into peptides in ways very different from those found in classical opioid peptides and retain kappa receptor affinity. This project involves two specific aims: 1) To explore conformationally restricted analogues of dynorphin, incorporating both short and longer range constraints, as ligands for kappa receptors, and 2) to explore novel sequences for affinity for kappa receptors using combinatorial approaches. These studies could result in the identification of ligands, potentially with novel structures, with high affinity and selectivity for kappa receptors. Such derivatives could be valuable pharmacological tools in increasing our understanding of how opioid ligands interact with their receptors at a molecular level.
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