Kalindjian S B, Dunstone D J, Low C M, Pether M J, Roberts S P, Tozer M J, Watt G F, Shankley N P
James Black Foundation, 68 Half Moon Lane, London SE24 9JE, UK.
J Med Chem. 2001 Apr 12;44(8):1125-33. doi: 10.1021/jm0010668.
In the course of structural explorations around a series of potent CCK2 receptor antagonists, it was noted that simple N-methylation of the indolic N-H in the parent molecule gave rise to behavior in vivo that was consistent with the compound acting as an agonist. Exploration in vitro confirmed this property, and it was shown that the agonist action could be blocked by the reference CCK2 receptor antagonist, L-365,260. Further examples of this type of modification were explored, and a common theme with regard to agonist behavior was uncovered. Some molecular modeling is also presented in an attempt to throw light on the nature of the ligand receptor interactions that may be giving rise to the differing properties of these, apparently, structurally similar molecules.
在对一系列强效CCK2受体拮抗剂进行结构探索的过程中，人们注意到母体分子中吲哚N-H的简单N-甲基化会导致体内行为，这与该化合物作为激动剂的作用一致。体外研究证实了这一特性，并且表明激动剂作用可被参考CCK2受体拮抗剂L-365,260阻断。对这类修饰的更多实例进行了探索，并发现了与激动剂行为相关的一个共同主题。还展示了一些分子建模，试图阐明可能导致这些明显结构相似的分子具有不同性质的配体-受体相互作用的本质。
