Discovery of new piperidine amide triazolobenzodiazepinones as intestinal-selective CCK1 receptor agonists

Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex

“…As previously reported 8, 9 , both triazolobenzodiazepinones, CE-326597 and PF-04756956 (Fig. 1), were highly efficacious agonists, stimulating maximal intracellular calcium responses not statistically different from those elicited by CCK at the CCK1R (Fig.…”

“…In an attempt to achieve this, the Pfizer group chose to take advantage of physicochemical properties of the molecules in their discovery series, seeking an appropriate balance of solubility and membrane permeability to result in adequate exposure of active drug to enteric neurons, and rapid hepatic clearance to minimize systemic exposure 8, 9 . They were also interested in low biliary clearance to allow prompt gallbladder relaxation, as occurs physiologically.…”

“…Both compounds were evaluated by reversed-phase HPLC with UV detection at 215 nm, and were found to be greater than 95 percent pure. These ligands have been reported to act as full agonists at the CCK1R 8, 9 . Cholecystokinin octapeptide (CCK-26-33, based on the numbering of CCK-33; also known as CCK-8) was purchased from Peninsula Laboratories (Belmont, CA).…”

“…In the current work, we have taken advantage of two triazolobenzodiazepinone agonists that have been reported to be full agonists of the CCK1R 8, 9 . Their chemical structures are distinct from the 1,5-benzodiazepine that has had its docking studied in greatest detail previously 5 , and these ligands possess unique pharmacological properties worthy of further analysis.…”

Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G protein‐coupled receptor structure and function

“…It is activated by CCK, a gastrointestinal hormone that is synthesized in the I‐cells of the small intestine and released in response to a meal (Gibbs et al, ; Chandra and Liddle, ). The role of CCK to reduce meal size has been demonstrated in animal models (Gibbs et al, ; Smith et al, ), as well as in humans (Kissileff et al, ; Smith and Gibbs, ), supporting the CCK 1 receptor as a potential target for the treatment of obesity (Bignon et al, ; Castillo et al, ; Berger et al, ; Elliott et al, ; Cameron et al, ). Although most studies have utilized CCK‐8, a form of this hormone that reduces meal size (satiation) without a consistent effect on meal frequency (satiety), more recent studies have shown that the predominant form of this hormone in the circulation is CCK‐58, which reduces both meal size and meal frequency (Reeve et al, ; Sayegh et al, ).…”