Characterization of YM022: its CCKB/gastrin receptor binding profile and antagonism to CCK-8-induced Ca2+ mobilization.
We investigated the antagonistic activity of (R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl) urea (YM022), a benzodiazepine derivative, at CCKB/gastrin receptors. This compound potently inhibited [125I]CCK-8 binding to rat brain CCKB/gastrin receptors with a Ki value of 0.26 nM, but it showed weak affinity for rat pancreas CCKA receptors (Ki = 270 nM). Selectivity for CCKB/gastrin receptors was 1000-fold greater than that for CCKA receptors. Changes in intracellular free Ca2+ concentration ([Ca2+]i) in response to CCK-8 were measured in a rat anterior pituitary cell line GH3 by fura-2 fluorometry. CCK-8 (1-100 nM) dose-dependently increased [Ca2+]i in these cells, whereas YM022 had no effect on baseline [Ca2+]i even at the highest concentration of 100 nM. YM022 inhibited the mobilization of [Ca2+]i elicited by 10 nM CCK-8 in a concentration-dependent manner with an IC50 value of 4 nM. In conclusion, YM022 is an extremely potent and highly selective antagonist of CCKB/gastrin receptors. This compound is therefore useful for studying the physiological and pharmacological roles of CCKB/gastrin receptors.
Drug Serendipity Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Y
Y
Saita
H
H
Yazawa
Y
Y
Honma
A
A
Nishida
K
K
Miyata
K
K
Honda
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020109:Devazepide; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism*
D001570:Benzodiazepinones; D007457:Iodine Radioisotopes; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C087260:YM 022; D002766:Cholecystokinin; D020109:Devazepide; D002118:Calcium