Synthesis of Novel Biologically Active Peptide Analogues that are Agonists at Opioid Receptors and Antagonists at Cholecystokinin Receptors
Committee ChairHruby, Victor J.
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PublisherThe University of Arizona.
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AbstractWe know that many disease states lead to changes in expressed proteins. Therefore, drug design and discovery based on normal states and single targets often is inadequate. The "system changes" that occurs must be considered in any treatment for the disease, clearly evident in neuropathic pain where opioids can actually heighten pain. To effectively treat diseases involving "systems changes" a new paradigm was recently introduced. In this new approach single peptide molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides were designed based on the overlapping pharmacophores of opioid and CCK ligands. The opioid/CCK analogues were synthesized and evaluated for their biological activities. Several analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. This study further modifies the RSA analogues to improve on the bioassays of the previous peptides.