SYNTHESIS AND STEREOCHEMICAL STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,3-DIOXOPERHYDROPYRIDO[1,2-C]PYRIMIDINE DERIVATIONS - POTENT AND SELECTIVE CHOLECYSTOKININ-A RECEPTOR ANTAGONISTS

The synthesis and stereochemical structure-activity relationships of a new class of potent and selective non-peptide cholecystokinin-a (CCK- A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyr imidine skeleton are described. The most potent member of this series of eight diastereoisomers, ryptophyl]amino]-1,3-dioxoperhydropyrido[1, 2-c]pyr displays nanomolar CCK-A receptor affinity and higher than 800 0-fold potency at the CCK-A than at the CCK-B receptor. As CCK-A antag onist, this compound inhibits the CCK-8-evoked amylase release from pa ncreatic acinar cells at a low concentration, similar to that of the t ypical antagonist Devazepide. Highly strict stereochemical requirement s for CCK-A receptor binding and selectivity have been found. The L-Tr p and the 4a,5-trans disposition of the bicyclic perhydropyrido[1,2-c] pyrimidine are essential for binding potency and selectivity.