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5-(Tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-Based Cholecystokinin Receptor Antagonists: Reversal of CCK<INF>1</INF> Receptor Subtype Selectivity toward CCK<INF>2</INF> Receptors
- Source :
- Journal of Medicinal Chemistry; October 2004, Vol. 47 Issue: 21 p5318-5329, 12p
- Publication Year :
- 2004
-
Abstract
- 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 CCK<INF>1</INF> 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 3-fold increase in the CCK<INF>1</INF> 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 CCK<INF>1</INF> to the CCK<INF>2</INF> 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 CCK<INF>2</INF> 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 CCK<INF>2</INF> receptor.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 47
- Issue :
- 21
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs6657202