Design and Synthesis of Orally-Active Galanin Agonists

Agonists and antagonists of the neuropeptide galanin have potential for therapeutic use as powerful analgetics and in Alzheimer's disease. A strategy that would make possible the development of galanin agonists and antagonists that are bioavailable in the brain would require the design of peptidominetic agents--mimics of galanin that are themselves non-peptides. Such compounds would have the lipid solubility required for penetration of the blood-brain barrier. Success in peptidominetic design, especially using computational chemistry, depends on an accurate method for prediction the three dimensional structure, both steric and electronic, of the parent peptide and also of the analogs and peptidomimetic design, since no three dimensional chemical information is readily derived from such structures. This is the case with design and synthesis of constrained peptides based on the computation of an accurate three dimensional structure for galanin. These constrained peptides represent three dimensional templates for the design, synthesis and testing of the peptidomimetics in Phase II. Algorithms to do this have been developed in our laboratories.