3,6-二氮杂双环[3.1.1]庚烷作为神经元烟碱型乙酰胆碱受体新型配体的合成
Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors.
作者信息
Murineddu Gabriele, Murruzzu Caterina, Curzu Maria M, Chelucci Giorgio, Gotti Cecilia, Gaimarri Annalisa, Legnani Laura, Toma Lucio, Pinna Gerard A
机构信息
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
出版信息
Bioorg Med Chem Lett. 2008 Dec 1;18(23):6147-50. doi: 10.1016/j.bmcl.2008.10.002. Epub 2008 Oct 5.
Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for alpha4beta2 (K(i) at alpha4beta2 ranging from 0.023 to 0.056 nM) versus alpha7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most alpha7alpha4beta2 selective term in receptor binding assays (alpha7alpha4beta2=1295). Moreover, compound 4d also had high affinity for the alpha4beta2 nAChR subtype (K(i)=1.2 nM) with considerably high selectivity (alpha7/alpha4beta2=23300).
合成了新型3,6-二氮杂双环[3.1.1]庚烷衍生物4a - f的α系列，并评估了它们对α4β2和α7尼古丁乙酰胆碱受体（nAChR）亚型的亲和力和选择性。当前研究结果显示，一些化合物（4a、4b和4c）对α4β2具有非常高的亲和力（α4β2的抑制常数K(i)范围为0.023至0.056 nM），相对于α7 nAChR亚型；在这些化合物中，3-(6-溴吡啶-3-基)-3,6-二氮杂双环[3.1.1]庚烷4c在受体结合试验中被发现是最具α7/α4β2选择性的（α7/α4β2 = 1295）。此外，化合物4d对α4β2 nAChR亚型也具有高亲和力（K(i)=1.2 nM），且具有相当高的选择性（α7/α4β2 = 23300）。
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