L-368935

The profile of an acidic series of benzodiazepine CCK-B receptor antagonists is described. The tetrazolyl urea derivative L-368,935 had high affinity (CCK-B IC50 0.1 nM) and was one of the most selective (CCK-B/CCK-A 10,000) CCK-B antagonists known. L-368,935 was a CCK-B antagonist with high affinity on the rat ventromedial hypothalamic slice preparation (Kb 0.6 nM) and also blocked pentagastrin-induced calcium mobilization in GH3 cells. L-368,935 had potent in vivo activity and antagonized pentagastrin-induced gastric acid secretion in the anesthetized rat and CCK-8S-induced aspartate release using microdialysis in the striatum of conscious rats. Activity within the central nervous system was confirmed by a mouse ex vivo binding assay and by direct measurement of the compound within the central nervous system using an HPLC assay. A second generation of CCK-B receptor antagonists such as L-368,935 will be important in determining the therapeutic potential of this class of compound in man.

Potent 3-arylureido-5-phenyl-1,4-benzodiazepines that are highly selective antagonists for the cholecystokinin-B (CCK-B) receptor are described.The two leading compounds derived from this investigation, L-368,935 and L-369,466, are water soluble, show high affinity for the CCK-B receptor from human cerebral cortex, are functional antagonists in vitro, and show no agonist activity.The brain penetrability of these compounds is relatively low, as determined by an ex vivo binding assay in the mouse.The oral bioavailability of these compounds, coupled with their favorable physicochem. and pharmacokinetic properties makes these analogs ideal candidates for the study of peripherally mediated physiol. effects attributed to CCK-B receptors.