Ennis M D, Stjernlöf P, Hoffman R L, Ghazal N B, Smith M W, Svensson K, Wikström H, Haadsma-Svensson S R, Lin C H
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
J Med Chem. 1995 Jun 9;38(12):2217-30. doi: 10.1021/jm00012a022.
A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a Ki of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.
制备了一系列强效且选择性的5-HT1A激动剂8-(二正丙基氨基)-6,7,8,9-四氢-3H-苯并[e]吲哚-1-甲醛（2b）（OSU191）的类似物，其中二丙基氨基被修饰以带有各种取代基。对这些化合物进行了体外和体内效应评估，包括确定这些类似物在5-HT1A、多巴胺D-2、多巴胺D-3、5-HT1Dα和5-HT1Dβ位点的受体结合谱。评估了其中几种类似物对利血平化大鼠的生化效应，特别是关于5-HTP和多巴脑内水平的体内变化。尽管大多数化合物对多巴胺D-2受体也表现出显著亲和力，但为本研究制备的几乎所有化合物在5-HT1A受体上都具有极高的活性。5-HT1Dα受体相对于5-HT1Dβ受体也表现出强烈的偏好。带有丁基戊二酰亚胺侧链的类似物S-7k对5-HT1A受体具有极高的选择性。尽管该化合物的Ki为0.6 nM，但它仅引起5-HTP脑内水平的适度变化。然而，在基于环磷酸腺苷的内在活性测定中测试时，该化合物并未表现为拮抗剂。
