The development of a competitive antagonist for a specific agonist ligand requires that the peptide ligand binds to the same receptor binding site as the agonist in a manner that blocks the agonist from binding to the receptor site but does not bind in a manner that activates the transduction mechanism. This chapter discusses approaches to the development of peptide receptor antagonists and three examples that show the principles involved in the antagonist design of peptide neurotransmitters and hormones can equally be applied to the development of growth factor inhibitors, enzyme inhibitors, antigen inhibitors, and any other system where molecular recognition is critical to a biological process. The development of peptide antagonists requires a highly interdisciplinary approach with excellent chemistry to design, synthesize and determine the structure of compounds of interest; state of the art analytical and biophysical facilities, including high field 2D and 3D nuclear magnetic resonance (NMR) spectroscopy and computer graphics and computer facilities; and comprehensive binding assays and in vitro and in vivo biological assays. Some of the analogues discussed in the chapter promise to provide unique new insights into the roles of opioid receptor in the control of pain, in the mechanisms of addiction and its management, and in determining the pharamcophore for μ opioid receptor antagonists.
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