L-365,260 is a selective antagonist of gastrin and brain type B cholecystokinin receptor (CCKB), with Ki values of 1.9nM and 2.0nM, respectively. L-365,260 interacts in a stereoselective and competitive manner with guinea pig stomach gastrin and brain CCK receptors. L-365,260 represents a potentially powerful new tool for investigating gastrin and brain CCKB receptors, and possibly their role in physiology and disease[1][2].
In vitro, pretreatment with 100nM L-365,260 for 1 hour completely blocked CCK-8S-induced calcium signal enhancement in the rat C6 glioma cells[3]. L-365,260 also inhibited the binding of 125I-BH-CCK-8S to rat C6 glioma cells with an IC50 of 9.9nM[3]. Administering 2.5μM L-365,260 for 5 days reduced the baseline growth of two human colon cancer cell lines, LoVo and C146, to 44% and 64% of the control group, respectively[4].
In vivo, in male albino Wistar rats, intraperitoneal administration of L-365,260 (0, 0.1, 1 and 10mg/kg) 15 minutes before testing decreased the startle amplitude on light+noise trials in a dose-dependent manner, while producing no effect on the average of the five baseline habituation (noise-alone) startle amplitudes[5]. In nude mice bearing AR42J xenografts, L-365,260 (5mg/kg/d) administered by oral gavage twice daily for 3-4 weeks inhibited the growth of AR42J tumors[4].
References:
[1] Lotti VJ, et, al. A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260. Eur J Pharmacol. 1989 Mar 21;162(2):273-80.
[2] Chung L, et, al. Cholecystokinin action on layer 6b neurons in somatosensory cortex. Brain Res. 2009 Jul 28;1282:10-9.
[3] Kaufmann R, Lindschau C, Schöneberg T, et al. Type B cholecystokinin receptors on rat glioma C6 cells. Binding studies and measurement of intracellular calcium mobilization. Brain Res. 1994;639(1):109-114.
[4] Watson S, Durrant L, Elston P, Morris D. Inhibitory effects of the gastrin receptor antagonist (L-365,260) on gastrointestinal tumor cells. Cancer. 1991;68(6):1255-1260.
[5] Josselyn SA, Frankland PW, Petrisano S, Bush DE, Yeomans JS, Vaccarino FJ. The CCKB antagonist, L-365,260, attenuates fear-potentiated startle. Peptides. 1995;16(7):1313-1315.
L-365,260是胃泌素和脑胆囊收缩素受体B亚型（CCKB）的选择性拮抗剂，Ki值分别为1.9nM和2.0nM。L-365,260以立体选择性和竞争性的方式与豚鼠胃泌素和脑CCK受体相互作用。L-365,260为研究胃泌素和脑CCKB受体及其在生理和疾病中的作用提供了潜在的强大新工具。
体外实验中，用100nM L-365,260预处理1小时可完全阻断CCK-8S在大鼠C6胶质瘤细胞中诱导的钙信号增强。此外，L-365,260还能抑制125I-BH-CCK-8S与大鼠C6胶质瘤细胞的结合，其IC₅₀值为9.9nM[3]。2.5μM L-365,260给药5天，降低了两种人类结肠癌细胞LoVo和C146的基线生长，分别降至对照组的44%和64%[4]。
体内实验中，在雄性白化Wistar大鼠中，于实验前15分钟腹腔注射L-365,260（0、0.1、1和10mg/kg）可剂量依赖性地降低光+噪声试验中的惊跳幅度，但对五次基线习惯化（仅噪声）试验的平均惊跳幅度没有影响[5]。在移植了AR42J的裸鼠中，每日两次灌胃给予L-365,260（5mg/kg/天），持续3-4周，抑制了AR42J肿瘤的生长[4]。