5-(tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based cholecystokinin receptor antagonists: Reversal of CCK1 receptor subtype selectivity toward CCK2 receptors

摘要

With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)- 1,3-dioxoperhydropyrido [1,2-c] pyrimidine-derived potent and highly selective CCK1 antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a Mold increase in the CCK1, binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK1 to the CCK2 receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK2 antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK2 receptor.