This multidisciplinary research project has as its general goals the design (using computer assisted modeling and pharmacophore evaluation) and synthesis (using modern synthetic organic and medicinal chemistry including asymmetric synthesis) of peptide mimetic that will interact with the delta receptor type and subtypes. Novel compounds will be sought with high selectivity and good potency for delta receptor types and subtypes. Specific goals include: 1) To design and synthesize novel conformationally constrained peptidominetics and pseudopeptides targeted for delta receptors; (2) To develop efficient syntheses of non-peptide or pseudopeptide scaffolds that can be appropriately modified for comprehensive structure-activity studies; 3) To utilize computer assisted modeling and conformational calculations in conjunction with published and derived pharmacophore models to develop delta ligands that are agonist and antagonists; 4) To develop appropriate analytical tools, including 2D nuclear magnetic resonance spectroscopy for structure determination; 5) To develop synthetic methods appropriate for radiolabeling of most promising leads; 6) To perform comprehensive biophysical studies to determine conformations of the most promising agonist and antagonist ligands; and 7) to prepare adequate supplies of our best compounds for our colleagues who perform pharmacological and biological studies. This proposal has great potential significance to human health. New modalities are needed for treatment of pain and addiction. Based on fundamental studies, it appears that delta receptors ligands can cause analgesia but without the serious side effects that accompany most current opioid analgesics, all of which act primarily at eta opioid receptors. These ligands also might be able to reverse the dependency due to use of eta or k receptor ligands. Such delta opioid could open up a new chapter in the treatment of pain and drug abuse.
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