DESIGN OF NOVEL LIGANDS WITH UNIQUE BIOLOGICAL PROFILES FOR NEUROPATHIC PAIN AND

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The long term goals of this research are to discover and design novel peptide and peptidomimetic ligands including bivalent ligands that can act as potent analgesics in chronic pain states (e.g. neuropathic pain, etc.) using new mechanisms of action, and that do not have the basic toxic side effects of current opioids such as respiratory depression and tolerance. For this purpose we are developing a comprehensive approach that includes computer assisted design of novel ligands; asymmetric synthesis of novel amino acids and p-turn mimetics; peptides and peptidomimetics with unique conformational and topographical properties; peptide ligands with unique biological properties; and use of a variety of biophysical studies of the conformational, topographical and dynamic properties of these ligands to help understand their unique biological properties and provide insights for further design. To pursue these goals we have the following Specific Aims: 1) To determine the structural features of non-opioid dynorphin A fragment peptides that may have interactions with a putative novel site of the bradykinin 2 receptor and activate it for a novel signaling pathway, and to develop antagonists for this novel binding site; 2) To design and develop bivalent ligands in a single structure that act as mu/delta opioid agonists and bradykinin receptor antagonists, to obtain ligands that can treat neuropathic pain states with minimal side effects of opiates; 3) To optimize structures of biphalin-related compounds that have mu/delta opioid activity but show minimal or none of undesirable toxic side effects of opioid ligands such as tolerance, and withdrawal symptoms; 4) To explore the design and synthesis of novel constrained amino acids, amino acid chimeras, and p-turn mimetics that can bias side chain groups at x1 and x2 torsional angles and/or in preferred backbone conformations for incorporation into novel ligands to enhance in vitro and in vivo biological properties; 5) To utilize computational and modeling methods and a number of biophysical tools including 2D NMR, CD, and plasmon waveguide resonance (PWR) spectroscopy to obtain novel insights into the relationships of conformational and topographical structure to biological activity, and to obtain insights into signal transduction by our novel ligands.