A second generation of non-peptide cholecystokinin receptor antagonists and their possible therapeutic potential.
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.
Freedman
S B
SB
Merck Sharp and Dohme Research Laboratories, Department of Biochemistry, Harlow, Essex, England.
Patel
S
S
Smith
A J
AJ
Chapman
K
K
Fletcher
A
A
Kemp
J A
JA
Marshall
G R
GR
Hargreaves
R J
RJ
Scholey
K
K
Mellin
E C
EC
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D015195:Drug Design; D015394:Molecular Structure; D011720:Pyrazoles / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011720:Pyrazoles; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines