Revel L, Ferrari F, Makovec F, Rovati L C, Impicciatore M
Rotta Research Laboratorium, Monza, Milano, Italy.
Eur J Pharmacol. 1992 Jun 5;216(2):217-24. doi: 10.1016/0014-2999(92)90363-9.
The antigastrinic activity, in vivo, of CR 2194 (R-4-(3-chlorobenzamido)-5-(8-azaspiro[4.5]decan-8-yl) -5-oxo pentanoic acid) was assessed in various animal species. CR 2194 antagonized pentagastrin-stimulated gastric acid secretion in the rat (ID50 = 11 mg/kg i.v.), dog (ID50 = 5.9 mk/kg i.v. or 28.8 mg/kg os) and cat (ID50 = 15.5 mg/kg i.v.). CR 2194, in the cat, inhibited both competitively and non-competitively the gastric acid secretion stimulated with increased doses of pentagastrin, with a pA2 of 4.89. In the rat and in the dog the antagonism seemed to be non-competitive and the respective pD'2 calculated were 4.54 and 4.42. The interaction of CR 2194 with the gastrin receptors appeared reversible, as demonstrated by the return to normal values of the acid output after the conclusion of the i.v. infusion, during pentagastrin continuous stimulation in the dog. The antigastrin activity was specific: CR 2194 was unable to antagonize the gastric acid secretion stimulated by carbachol or histamine in the rat up to the dose of 100 mg/kg. CR 2194 was effective to antagonize the gastric acid secretion stimulated by gastrin release after meal ingestion in the Heidenhain pouch dog model. The ID50 calculated was 2.89 mg/kg after oral administration. All these characteristics make CR 2194 an important compound in the investigation of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.
在多种动物物种中评估了CR 2194（R-4-（3-氯苯甲酰胺基）-5-（8-氮杂螺[4.5]癸烷-8-基）-5-氧代戊酸）的体内抗胃泌素活性。CR 2194拮抗大鼠（静脉注射半数抑制剂量（ID50）=11毫克/千克）、狗（静脉注射ID50 = 5.9微克/千克或口服28.8毫克/千克）和猫（静脉注射ID50 = 15.5毫克/千克）中五肽胃泌素刺激的胃酸分泌。在猫中，CR 2194对五肽胃泌素剂量增加所刺激的胃酸分泌既有竞争性抑制又有非竞争性抑制，其拮抗常数（pA2）为4.89。在大鼠和狗中，这种拮抗作用似乎是非竞争性的，计算得出的各自的表观解离常数（pD'2）分别为4.54和4.42。在狗进行五肽胃泌素持续刺激期间，静脉输注结束后胃酸分泌恢复到正常水平，这表明CR 2194与胃泌素受体的相互作用似乎是可逆的。抗胃泌素活性具有特异性：在大鼠中，高达100毫克/千克剂量的CR 2194无法拮抗卡巴胆碱或组胺刺激的胃酸分泌。在海登海因小胃狗模型中，CR 2194能有效拮抗餐后胃泌素释放所刺激的胃酸分泌。口服给药后计算得出的ID50为2.89毫克/千克。所有这些特性使CR 2194成为研究胃泌素生物学效应的重要化合物以及一种有诊断或治疗用途潜力的药物。
