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A Second Generation of Non‐Peptide Cholecystokinin Receptor Antagonists and Their Possible Therapeutic Potential
Author(s) -
FREEDMAN S. B.,
PATEL S.,
SMITH A. J.,
CHAPMAN K.,
FLETCHER A.,
KEMP J. A.,
MARSHALL G. R.,
HARGREAVES R. J.,
SCHOLEY K.,
MELLIN E. C.,
DiPARDO R. M.,
BOCK M. G.,
FREIDINGER R. M.
Publication year - 1994
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1994.tb44079.x
Subject(s) - library science , chemistry , pharmacology , medicine , computer science
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.