Seven-transmembrane (7-TM) receptors are found throughout the body and count among their members the primary targets for most neurotransmitters and peptide hormones. Due to the large number of 7-TM receptors and the flexibility of most 7-TM ligands, many agonists for a particular 7-TM receptor site have the ability to bind and activate numerous other sites and hence give rise to a variety of side effects. Clearly, an understanding of what factors govern the binding of hormones to particular 7-TM receptors is essential for developing potential drug candidates that can discern between related receptor sites. The proposed research aims to examine the overall utility of a series of lactam-based, conformationally constrained peptide mimetics for """"""""mapping"""""""" the three-dimensional requirements of 7-TM receptors. Specifically, the thyrotropin releasing hormone 7-TM receptor TRH-R and the substance P 7-TM receptor NK1 will be studied. In both cases, a pair of models exist for the conformation of the hormone responsible for binding, and in both cases conformationally restricted analogs capable of differentiating between the models have been designed. In the proposed work, these restricted analogs will be synthesized and tested for both their affinity and potency for the appropriate 7-TM receptor. The biological data will then be used to draw conclusions about the receptor bound conformation of the hormone. One of the key problems in any such study involves the synthesis of the desired constrained analogs. Many studies of this nature fail when the required analogs can not be made. Even when the analogs are synthesized, if the syntheses are too complex, then the general applicability of the approach is severely limited. Since the long range objective of this work is to develop generally useful strategies for probing the relationship between the predicted and actual biological activity of peptide conformations, one of the primary objectives of the proposed research will be to develop new synthetic methodology for rapidly constructing lactam- based peptide mimetics.
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