The long term goals of this research project are to find novel ligands with novel biological profiles that will mediate severe pain without the toxic side effects of current uploads used in clinical medicine. Recent physiological, pharmacological and molecular biological evidence provide evidence that in persistent pain states the expression and activity of neuropeptides and other neuromodulators are different than in normal physiological states. This creates new paradigms for development of opioid ligands with potent analgesic properties but without some of the toxic side effects of current uploads. In this muIti-disciplinary grant involving three different laboratories we propose to exploit recent developments in de novo design, combinatorial chemistry, opioid pharmacology, physiology and molecular biology to develop new classes of non-peptide peptidomimetic ligands that will test the hypothesis that ligands with a profile of mu agonist and delta antagonist activities and which can cross the blood-brain-barrier will show outstanding antiallodynic and antinociceptive efficacy in chronic neuropathic pain states and will not demonstrate tolerance. Furthermore, to more clearly examine the mechanism of action of novel uploads, we wish to develop novel potent highly selective u antagonist and 5 antagonists that cross the BBB and do not have the long term toxicity of current selective antagonists.
Our Specific Aims are: 1. To design, synthesize and evaluate in vitro, novel non-peptide ligands with u agonist/6 antagonist biological activity that cross the BBB. 2. To examine the potency and efficacy of the novel ligands using radioligand binding, GTP gamma S, MVD and GPI assays. 3. To demonstrate antihyperalgesic, antiallodynic and antinociceptive efficacy of p agonist/6 antagonist following systemic administration. 4. To demonstrate a lack of antinociceptive tolerance following repeated systemic administration. 5. To utilize computer aided molecular modeling, conformational analysis, biophysical method (NIVIR, CD, X-ray, etc.) to determine the bioactive conformations of our best ligands, and then to compare their topographical structures to see their relationships to the peptide pharmacophores, so that an approach to true non-peptide peptidomimetics can be achieved. 6. To design and evaluate novel non-peptide ligands that are systemically active delta antagonists; and 7. To design and evaluate novel non-peptide ligands that are systemically active 5 antagonists. Novel new ligands with novel mechanisms of pain control that provide new approaches to unmet needs in pain control will result from these studies.
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