Potency of CR 1409, a new proglumide analog, on cholecystokinin-mediated behaviors and receptor binding

Behavioral and receptor binding techniques were employed to evaluate the potency of CR 1409, a new analog of proglumide, as a cholecystokinin antagonist. CR 1409, at doses of 1 mg/kg i.p. in mice, effectively blocked the inhibition of feeding and exploratory behaviors induced by cholecystokinin. In rats, CR 1409 alone, at doses of 1 and 10 mg/kg, did not affect feeding or exploratory behaviors, but at 25 mg/kg alone, CR 1409 reduced food intake and exploratory behaviors, suggesting a mixed agonist-antagonist profile. On these several behavorial parameters, CR 1409 antagonized peripherally administered cholecystokinin with 10-1000 times greater potency than that reported for proglumide (Crawley et al., J. Pharmac. Exp. Ther. 236, 320-330, 1986). In binding to pancreatic cholecystokinin membranes, CR 1409 was more than 100,000-times more potent than that reported for proglumide (Rovati, Scand. J. Gastroenterol. 11, 113-118, 1976). CR 1409 inhabited binding of 125-I-cholecystokinin octapeptide in mouse parcreatic and brain membranes with IC₅₀ values of 13.7 nM and 2.6 μM, respectively, demonstrating its selectivity for peripheral-type CCK receptors.