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

1987; Elsevier BV; Volume: 10; Issue: 4 Linguagem: Inglês

10.1016/0197-0186(87)90083-0

1872-9754

Maria-Th. Kaltwasser, Barbara Petrack, J. N. Crawley,

Peptidase Inhibition and Analysis

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.