A series of conformationally restricted cholecystokinin octapeptide (CCK8) analogs will be synthesized. Two approaches will be used to introduce reverse turns into the molecule to mimic the solution, and possibly bioactive, conformation of CCK8. These will include cyclization via side chain to side chain and side chain to backbone covalent bond formation and introduction of a bicyclic ring system that simulates a type II'Beta-turn (peptidomimetic analogs). In the latter case the rigid framework will be substituted with the appropriate side chain functionalities corresponding to the residues being replaced. These side chains will be incorporated via stereospecific Alpha-alkylation of L-tyrosine and L-tryptophan. The biological activity of these compounds will be assayed by determining their ability to produce contractions in the isolated guinea pig gallbladder and dispersed acinar cells from guinea pig pancreas. Correlations between the induced conformation and observed biological activity will be made and used to design other conformationally restricted CCK8 analogs. These compounds will be useful in further defining the conformational and dynamic properties responsible for interaction of CCK8 with its receptor(s) and transduction of the biological message. The possibility exists for development of more potent and specific anatagonists of CCK8 which will be important in determining its physiological role(s).
