Arvidsson L E, Karlén A, Norinder U, Kenne L, Sundell S, Hacksell U
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, University of Uppsala, Sweden.
J Med Chem. 1988 Jan;31(1):212-21. doi: 10.1021/jm00396a034.
The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.
通过实验（核磁共振光谱）和理论（分子力学和MNDO计算）方法相结合，研究了两类5-羟色胺（5-HT）受体激动剂的构象特征，即单酚型N，N-二烷基化2-氨基四氢萘和反式-2-苯基环丙胺。此外，还对选定的构象计算了分子静电势，并通过合成前体的X射线晶体学确定了强效5-HT受体激动剂（+）-顺式-8-羟基-1-甲基-2-（二正丙基氨基）四氢萘的绝对构型为1S，2R。根据5-HT受体激活的构象、空间和电子要求对所得结果进行了讨论。结果表明，5-HT受体激动剂（1R，2S）-2-（2-羟基苯基）-N，N-二正丙基环丙胺[（1R，2S）-4]及其3-羟基异构体（1R,2S）-5的不同构象能够激活5-HT受体。与8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT；1）相比，2、4和5的立体选择性大幅提高，这可根据空间因素得到合理的解释。构象因素似乎是导致1的反式C1-甲基取代衍生物无法激活HT受体的原因。
