BIOCHEMICAL CHARACTERIZATION OF OPIOID LIGANDS AND RECEPTORS

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The treatment of pain associated with surgery, trauma and many diseases states is an essential part of medical practice. Opinoids such as morphine remain the most effective drugs for the treatment of severe pain and are widely used for this purpose despite haveing many serious gastrointestinal, cardiovascular and respiratory side effects. Worst still, these drugs produce a state of physical dependence after repeated use that can lead to addiction. The most effective drugs acting at delta opioid receptors are peptides that cannot enter the central nervous system after conventional routes of administration. New compounds must be made if they are to be useful in the clinic. This proposal seeks to answer the questin, "Can opioid peptide ligands selective for the delta receptor be divided into groups distinguished by their ability to bind this receptor in different ways?" While it is well understood that these drugs must bind opioid receptors to produce effects such as analgesia, marked differences in their chemical structures strongly suggest that they must do so in different ways. If, as this implies, there are different ways for these drugs to bind to the same receptor, then how does this difference affect the way they act? Drugs bind to receptors through contacts with specific receptor amino acids that are in turn encoded by DNA. We propose to modify delta opioid receptors to have amino acid sequences obtained from other opioid receptors (mu an kappa) substituted for existing delta receptor sequences. Such an artificial receptor is called a chimera and it would have drug recognition properties derived from both parent receptors. This kind of large scale modification can be used to narrow down where in the receptor drugs are bound. Individual contacts between receptor amino acids and functional groups of a drug can be determined by selectively changing the DNA sequence encoding a single amino acid using the technique of site-directed mutagenesis. With these two tools we intend to (1) show that chemically defined groups of opioid drugs consistently use particular groups of aiminoacids for delta receptor binding and (2) that the use of these different "recognition sites" is responsible for specific properties of these drugs. This information could revolutionize how new opioid drugs are designed since it defines these drugs by how they interact with delta receptors rather than by their chemical structures.