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The relative ability of a norleucine substituted cholecystokinin (CCK) analogue, U-67827E, to interact with CCK receptors and to inhibit food intake was examined across a variety of paradigms. U-67827E and CCK had identical in vitro potencies as demonstrated by their ability to induce pyloric contractions or competitively inhibit [125I]CCK-8 binding to type A and B CCK receptors. However, the in vivo potency of U-67827E was significantly greater than that of CCK-8. In rats, U-67827E inhibited food intake with 10-100 times the potency of CCK. In rhesus monkeys, U-67827E produced significantly greater inhibitions of daily food intake and did so in a dose-dependent manner with no evidence of compensation or tolerance. U-67827E also inhibited gastric emptying for significantly longer durations than CCK. Together these results demonstrate that CCK analogues with increased in vivo bioavailability can affect food intake beyond a single meal.
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