Patel S, Smith A J, Chapman K L, Fletcher A E, Kemp J A, Marshall G R, Hargreaves R J, Ryecroft W, Iversen L L, Iversen S D
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, Great Britain.
Mol Pharmacol. 1994 Nov;46(5):943-8.
A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidines), which contain a cationic solubilizing group and which are antagonists for the cholecystokinin (CCK)-B receptor, have been identified. Optimization of this series led to the identification of an azabicyclononane amidine, L-740,093 [N-[(3R)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1-methyl-2- oxo- 1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea], that bound with high affinity of CCK-B receptors from guinea pig cerebral cortex (IC50 of 0.1 nM) and had a CCK-B/CCK-A receptor selectivity of 16,000. In comparison, L-365,260 had 85-fold lower affinity (8.5 nM) and was only 87-fold selective for CCK-B over CCK-A receptors. L-740,093 bound with high affinity to guinea pig gastrin receptors in vitro (IC50 of 0.04 nM). Electrophysiological studies on slices of rat ventromedial hypothalamic nucleus showed that L-740,093 produced rightward shifts of the concentration-response curve for the CCK-B receptor agonist pentagastrin (Kb of 0.06 nM). L-740,093 blocked pentagastrin-induced gastric acid secretion in anesthetized rats with a 50% inhibitory dose of 0.01 mg/kg, intraperitoneally, showing 100-fold greater activity, compared with L-365,260 (50% inhibitory dose of 1 mg/kg, intraperitoneally). An ex vivo binding assay in mice was used to investigate the interaction of L-740,093 with central CCK binding sites. After intravenous administration, L-740,093 inhibited ex vivo binding dose dependently, with a 50% effective dose of 0.2 mg/kg. These studies demonstrate that L-740,093 is the most potent and selective CCK-B antagonist yet described and that it has excellent central nervous system penetration.
已鉴定出一系列新型的5-氨基-1,4-苯并二氮杂卓-2-酮衍生物（脒类），其含有阳离子增溶基团且是胆囊收缩素（CCK）-B受体的拮抗剂。对该系列进行优化后得到了氮杂双环壬烷脒L-740,093 [N-[(3R)-5-(3-氮杂双环[3.2.2]壬烷-3-基)-2,3-二氢-1-甲基-2-氧代-1H-1,4-苯并二氮杂卓-3-基]-N'-(3-甲基苯基)脲]，它与豚鼠大脑皮层的CCK-B受体具有高亲和力（IC50为0.1 nM），并且CCK-B/CCK-A受体选择性为16,000。相比之下，L-365,260的亲和力低85倍（8.5 nM），对CCK-B受体与CCK-A受体的选择性仅为87倍。L-740,093在体外与豚鼠胃泌素受体具有高亲和力（IC50为0.04 nM）。对大鼠腹内侧下丘脑核切片的电生理研究表明，L-740,093使CCK-B受体激动剂五肽胃泌素的浓度-反应曲线向右移动（Kb为0.06 nM）。L-740,093以0.01 mg/kg的腹腔注射半数抑制剂量阻断了麻醉大鼠中五肽胃泌素诱导的胃酸分泌，与L-365,260（腹腔注射半数抑制剂量为1 mg/kg）相比，活性高100倍。在小鼠中进行的体外结合试验用于研究L-740,093与中枢CCK结合位点的相互作用。静脉给药后，L-740,093剂量依赖性地抑制体外结合，半数有效剂量为0.2 mg/kg。这些研究表明，L-740,093是迄今所描述的最有效和选择性最高的CCK-B拮抗剂，并且它具有出色的中枢神经系统渗透性。
