Witter A, Greven H M, Wied D D E
J Pharmacol Exp Ther. 1975 Jun;193(3):853-60.
The effect of substitutions in adrenocorticotropin (ACTH4-9) on extinction of pole-jumping avoidance behavior in intact rats was investigated systemically at two-dose levels. Simultaneous introduction of 4-methionine sulfoxide and 5-D-lysine, in combination with 9-phenylalanine, led to a 1000-fold increase in behavioral potency. The same substitutions induced a 1000-fold decrease in melanocyte-stimulating hormone activity. Incubations of 14-C-labeled ACTH4-9 analogs, prepared by reductive methylation, were carried out with plasma and brain extracts. The resulting metabolites were separated by paper electrophoresis and paper chromatography. The concentrations of nonmetabolized hexapeptides, which appeared to be almost entirely responsible for behavioral activity, were determined as a function of incubation time. The in vitro half-life of intact hexapeptides correlated with their behavioral activity. Therefore, the increase in behavioral potency as a result of amino acid substitutions can be explained, at least partly, by increased resistance against biotransformation.
在两个剂量水平下，系统研究了促肾上腺皮质激素（ACTH4 - 9）中的取代基对完整大鼠跳杆回避行为消退的影响。同时引入4 - 甲硫氨酸亚砜和5 - D - 赖氨酸，并结合9 - 苯丙氨酸，导致行为效力增加1000倍。相同的取代基使促黑素细胞激素活性降低1000倍。通过还原甲基化制备的14 - C标记的ACTH4 - 9类似物与血浆和脑提取物进行孵育。所得代谢产物通过纸电泳和纸色谱法分离。确定了似乎几乎完全负责行为活性的未代谢六肽的浓度与孵育时间的关系。完整六肽的体外半衰期与其行为活性相关。因此，氨基酸取代导致的行为效力增加至少部分可以通过对生物转化的抗性增加来解释。
