Pharmacological profile 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 new potent and selective gastrin/cholecystokinin-B receptor antagonist, in vitro and in vivo.
(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishida
A
A
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Miyata
K
K
Tsutsumi
R
R
Yuki
H
H
Akuzawa
S
S
Kobayashi
A
A
Kamato
T
T
Ito
H
H
Yamano
M
M
Katuyama
Y
Y
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D018723:Bethanechol; D001626:Bethanechol Compounds / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000378:metabolism
D001570:Benzodiazepinones; D001626:Bethanechol Compounds; D007211:Indoles; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D018723:Bethanechol; D001569:Benzodiazepines; C065599:PD 134308; C087260:YM 022; C058121:L 365260; D008536:Meglumine; D006632:Histamine; D010418:Pentagastrin; D012844:Sincalide