Garbrecht W L, Marzoni G, Whitten K R, Cohen M L
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
J Med Chem. 1988 Feb;31(2):444-8. doi: 10.1021/jm00397a030.
A series of (8 beta)-6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid cycloalkyl esters were prepared and examined for blockade of vascular 5HT2 receptors. The antagonist in this series that had the highest 5HT2 receptor affinity was (8 beta)-6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid cyclohexyl ester. This compound was therefore chosen as the basic backbone of a structure-activity study to determine what effect different N1-substituents, N6-substituents, and ester ring substituents had on 5HT2 receptor affinity. Maximal 5HT2 receptor affinity was obtained when the N1-substituent was isopropyl, the N6-substituent was methyl, and there was a hydroxy or keto substituent in the 4-position of the ester cyclohexyl ring.
制备了一系列(8β)-6-甲基-1-(1-甲基乙基)麦角灵-8-羧酸环烷基酯，并检测其对血管5HT2受体的阻断作用。该系列中5HT2受体亲和力最高的拮抗剂是(8β)-6-甲基-1-(1-甲基乙基)麦角灵-8-羧酸环己酯。因此，选择该化合物作为构效关系研究的基本骨架，以确定不同的N1-取代基、N6-取代基和酯环取代基对5HT2受体亲和力有何影响。当N1-取代基为异丙基、N6-取代基为甲基且酯环己基环的4-位有羟基或酮基取代基时，可获得最大的5HT2受体亲和力。
