We propose to continue to develop a rational approach to the design, synthesis and biological evaluation of cholecystokinin (CCK) analogues that will possess high potency and receptor selectivity for CCK-A and CCK-B receptors that directly or indirectly regulate gastrointestinal function. A multidisciplinary program that includes modern computer assisted drug design, conformational analysis using NMR, other biophysical tools and computational methods, the latest methodology in synthetic amino acid and peptide chemistry, and careful analysis of structure-biological activity relationships will be utilized in this research. Both agonist and antagonist analogues are desired.
The specific aims can be summarized as follows: 1) design, synthesis and evaluation of highly selective CCK-B analogues; 2) design, synthesis and evaluation of highly selective CCK-A analogues; 3) if a good lead emerges, develop CCK antagonists based on peptide structure; 4) perform careful 2D nuclear magnetic resonance spectroscopy experiments, conformational calculations and related biophysical studies and computer modeling to determine conformation(s) of selective analogues; 5) bring in topographical design features when possible; 6) provide synthetic and analytical services for other members of the Program Project for some peptides needed in their studies. Our goal is to obtain highly potent and receptor selective CCK analogues that will allow new insights into the role of CCK in the normal gut, and in the use of CCK agonists and antagonists for the treatment of gastrointestinal disorders. Effort will be made to determine those structural features of CCK important for differentiating CCK-B receptors and gastrin receptors, and those that differentiate receptor subtypes of the CCK-A and CCK-B receptors, if any.
Showing the most recent 10 out of 14 publications
