Makovec F, Peris W, Revel L, Giovanetti R, Mennuni L, Rovati L C
Rotta Research Laboratorium, Monza, Milan, Italy.
J Med Chem. 1992 Jan;35(1):28-38. doi: 10.1021/jm00079a003.
New (R)-4-benzamido-5-oxopentanoic acid derivatives were synthesized by a stereoconservative procedure and evaluated in vitro for their capacity to inhibit the binding of 125I-CCK-8 to either rat peripheral (CCK-A) or central (CCK-B) CCK receptors, or the binding of [3H]pentagastrin to rabbit gastric glands, as well as to inhibit, in vivo, the acid secretion induced by pentagastrin infusion in the perfused rat stomach. The parent compound of this series (lorglumide) is the first nonpeptidic, potent and selective antagonist of the CCK-A receptor. Chemical manipulations of the structure of lorglumide led to the discovery of selective antagonists of the CCK-B/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives exhibit different affinities with rabbit gastric gland cells and rat cortex membranes, suggesting that the stomach gastrin receptor (arbitrarily termed CCK-B1 receptor) is not as closely related to the CCK central receptor (termed CCK-B2) as previously hypothesized. The antigastric activity of the most potent compound of the series, i.e. (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid (compound 28, CR 2194) was further evaluated in vivo: in the first hour after administration the compound inhibits acid secretion induced by pentagastrin infusion, in both cat and dog (in the cat with gastric fistula and in the dog with Heidenhain pouch), with ID50s (mg/kg) of 15.5 (iv) (cat), 8.7 (IV) (dog) and 24.2 (oral) (Heidenhain dog). The characteristics of CR 2194, that is, the selectivity for the gastrin receptor, the simple nonpeptidic molecular structure, and the activity after oral administration, indicate that this compound is a useful tool in the study of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.
通过立体保守方法合成了新型（R）-4-苯甲酰胺基-5-氧代戊酸衍生物，并在体外评估了它们抑制[125I]（BH）-CCK-8与大鼠外周（CCK-A）或中枢（CCK-B）CCK受体结合的能力，以及抑制[3H]五肽胃泌素与兔胃腺结合的能力，同时在体内评估了它们抑制灌注大鼠胃中五肽胃泌素输注诱导的胃酸分泌的能力。该系列的母体化合物（洛谷胺）是首个非肽类、强效且选择性的CCK-A受体拮抗剂。对洛谷胺结构进行化学操作后发现了CCK-B/胃泌素受体的选择性拮抗剂。讨论了构效关系。其中一些新衍生物对兔胃腺细胞和大鼠皮层膜表现出不同的亲和力，这表明胃胃泌素受体（任意称为CCK-B1受体）与CCK中枢受体（称为CCK-B2）的关系并不像先前假设的那样密切。对该系列中最有效化合物，即（R）-4-（3,5-二氯苯甲酰胺基）-5-（8-氮杂螺[4.5]癸-8-基）-5-氧代戊酸（化合物28，CR 2194）的抗胃活性进行了进一步的体内评估：给药后的第一小时内，该化合物在猫和狗（猫为胃瘘模型，狗为海登海因小胃模型）中均抑制五肽胃泌素输注诱导的胃酸分泌，静脉注射的半数抑制剂量（ID50，mg/kg）分别为15.5（猫）、8.7（狗）和口服给药时24.2（海登海因狗）。CR 2194的特性，即对胃泌素受体的选择性、简单的非肽类分子结构以及口服活性，表明该化合物是研究胃泌素生物学效应的有用工具，也是一种潜在的诊断或治疗药物。
