Misner J W, Garbrecht W L, Marzoni G, Whitten K R, Cohen M L
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285.
J Med Chem. 1990 Feb;33(2):652-6. doi: 10.1021/jm00164a029.
A series of (8 beta)-6-methylergoline amide derivatives was synthesized with various alkyl substituents in the N1-position in order to evaluate their effectiveness in blocking vascular 5HT2 receptors. The influence of both the N1 substituent and amide derivative proved to be of great importance on binding affinities to vascular 5HT2 receptors. Within each series of amides, however, maximum affinity was achieved with an N1-isopropyl substituent (14, 18, 26, 38, and 41; all with 2.7-50 times greater affinity than their N1-H analogues), with the exception of two cases (22 and 37) in the cyclohexylamide derivatives wherein N1-methyl equalled the isopropyl in potency. Other than these exceptions, affinities followed the pattern of H less than Me less than Et less than iPr, with potencies falling off with larger alkyl substituents.
合成了一系列在N1位带有不同烷基取代基的(8β)-6-甲基麦角灵酰胺衍生物，以评估它们阻断血管5-羟色胺2（5HT2）受体的有效性。结果表明，N1取代基和酰胺衍生物对与血管5HT2受体的结合亲和力都非常重要。然而，在每一系列酰胺中，除环己基酰胺衍生物中的两个例子（22和37）外，N1-异丙基取代基能实现最大亲和力（化合物14、18、26、38和41；其亲和力均比相应的N1-H类似物高2.7至50倍），在这两个例子中N1-甲基的效力与异丙基相当。除这些例外情况外，亲和力遵循H＜Me＜Et＜iPr的模式，且随着烷基取代基增大，效力逐渐降低。
