BIOCHEMICAL AND PHARMACOLOGICAL PROFILES OF LOXIGLUMIDE, A NOVEL CHOLECYSTOKININ-A RECEPTOR ANTAGONIST

Loxiglumide obenzamido)-N-(3-methoxypropyl)-N-pentylglutaramic acid, C AS 107097-80-3, CR1505) is a new derivative of glutaramic acid. Radiol igand displacement assay was performed to characterize the selectivity of loxiglumide to CCK-A (cholecystokinin-A) receptor (rat pancreas an d bovine gallbladder) and CCK-B/gastrin receptors (guinea pig cerebral cortex and guinea pig gastric parietal cell). And tissue bioassay was performed to investigate the effect of the compound on contractions o f the guinea pig gallbladder and ileum. Loxiglumide inhibited I-125-CC K-8 binding to rat pancreatic and bovine gallbladder membranes with IC 50 values of 195 and 77.1 nmol/l, respectively. Loxiglumide also inhib ited I-125-CCK-8 binding to guinea pig cerebral cortex membranes and p arietal cells with IC50 values of 12363 and 15455 nmol/l, respectively In addition, loxiglumide inhibited I-125-gastrin binding to guinea pi g parietal cells with IC50 values of 6134 nmol/l. These results indica te that the affinity of loxiglumide to CCK-A receptor is at least 63 t imes greater than that to CCK-B/gastrin receptors. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig gallbladder and ileum further demonstrate that loxiglumide acts as a competitive CCK antagonist with a high affinity to these tissues (gall bladder, pa(2): 6.71).