Welch W M, Harbert C A, Weissman A, Koe B K
J Med Chem. 1986 Oct;29(10):2093-9. doi: 10.1021/jm00160a050.
Compounds derived from 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b]indole are consistently efficacious in displacing [3H]spiroperidol from striatal dopamine receptors in vitro. Derivatives bearing substituents at position 2, particularly those derived from butyrophenone moieties, are exceptionally potent in vivo. Compounds from the corresponding 4a,9b-cis series are substantially less potent in both in vivo and in vitro assays of neuroleptic activity. Although the cis and trans derivatives have, in some conformations, similar basic nitrogen atom to aromatic ring separations of about 5.1 A, the distance at which the basic nitrogen atom lies above or below the plane of the aromatic ring differs substantially between the two series. Consideration of these results in terms of this and earlier work indicates that the out-of-plane distance for the basic nitrogen in neuroleptic molecules may range from about 0 to about 0.90 A but may be optimized at about 0.55 A.
源自4a,9b-反式-2,3,4,4a,5,9b-六氢-1H-吡啶并[4,3-b]吲哚的化合物在体外从纹状体多巴胺受体置换[3H]螺哌啶醇方面始终有效。在2位带有取代基的衍生物，特别是那些源自丁酰苯部分的衍生物，在体内具有异常高的活性。相应的4a,9b-顺式系列的化合物在体内和体外抗精神病活性试验中的效力明显较低。尽管顺式和反式衍生物在某些构象中具有相似的碱性氮原子到芳环的间距，约为5.1埃，但两个系列中碱性氮原子位于芳环平面上方或下方的距离有很大差异。根据这项工作和早期工作对这些结果的考虑表明，抗精神病分子中碱性氮的平面外距离可能在约0至约0.90埃范围内，但可能在约0.55埃时达到最佳。
