Elsner Jan, Boeckler Frank, Davidson Kathryn, Sugden David, Gmeiner Peter
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Bioorg Med Chem. 2006 Mar 15;14(6):1949-58. doi: 10.1016/j.bmc.2005.10.042. Epub 2005 Nov 15.
Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT1 and MT2 receptors. Shifting the methoxy group from position 5 to 2 of the 7a-azaindole ring led to a substantial reduction of MT1 binding when MT2 recognition was maintained. We theoretically investigated the hypothesis whether the 2-methoxy function of the azamelatonin analogue 27 is able to mimic the 5-methoxy group of the neurohormone by directing its 2-methoxy function toward the methoxy binding site. DFT calculations and experimental binding differences of analogue compounds indicate that the energy gained by forming the methoxy-specific hydrogen-bond interaction should exceed the energy required for adopting an alternative conformation.
利用1,3-偶极环加成反应合成7a-氮杂吲哚核，已合成褪黑素类似物并针对人和两栖动物的褪黑素受体进行了测试。在杂环部分的2位引入苯基取代基显著增加了对MT1和MT2受体的结合亲和力。当保持MT2识别时，将甲氧基从7a-氮杂吲哚环的5位移至2位导致MT1结合显著降低。我们从理论上研究了氮杂褪黑素类似物27的2-甲氧基官能团是否能够通过将其2-甲氧基官能团导向甲氧基结合位点来模拟神经激素的5-甲氧基基团这一假设。类似物化合物的密度泛函理论计算和实验结合差异表明，通过形成甲氧基特异性氢键相互作用获得的能量应超过采用替代构象所需的能量。
