5-(PIPERIDIN-2-YL)-1,4-BENZODIAZEPINES AND 5-(HOMOPIPERIDIN-2-YL)-1,4-BENZODIAZEPINES - HIGH-AFFINITY, BASIC LIGANDS FOR THE CHOLECYSTOKININ-B RECEPTOR

The design, synthesis, and biological activity of a series of high-aff inity, basic ligands for the cholecystokinin-B receptor are described. The compounds, which incorporate a piperidin-2-yl or a homopiperidin- 2-yl group attached to C-5 of a benzodiazepine core structure, are sub stantially more basic (e.g., 9d, pK(a)=9.48) than previously reported antagonists based on 5-amino-1,4-benzodiazepines (e.g., 5, pK(a)=7.1) and have improved aqueous solubility. In view of their basicity, it wo uld be tempting to speculate that the present series of compounds migh t be binding to the CCK-B receptor in their protonated form. Compounds such as 9d,e and 10d showed high affinity for this receptor (IC50 < 2 .5 nM) and very good selectivity over CCK-A (CCK-A/CCK-B > 2000), even as the racemates. Additionally, a significantly improved in vivo half -life was observed for a selection of compounds compared to the clinic al candidate L-365,-260 (1).