新型 N-芳基烟酰胺衍生物：以 3,6-二氮杂双环[3.1.1]庚烷作为配体的神经元乙酰胆碱受体研究进展。
Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors.
机构信息
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100, Sassari, Italy.
CNR, Institute of Neuroscience, Via Vanvitelli 32, 20129, Milano, Italy.
出版信息
Eur J Med Chem. 2019 Oct 15;180:51-61. doi: 10.1016/j.ejmech.2019.06.079. Epub 2019 Jul 5.
We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with αβKi value of 10 pM and a very high α/αβ selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for αβ nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.
我们设计合成了一个 3-取代-3,6-二氮杂双环[3.1.1]庚烷的小文库，评估了其对神经元烟碱型乙酰胆碱受体（nAChRs）的亲和力。在所合成的化合物中，5-(3,6-二氮杂双环[3.1.1]庚烷-3-基）-N-(2-氟苯基）烟酰胺 43 被证明是最有趣的化合物，其 αβKi 值为 10 pM，具有非常高的 α/αβ 选择性。此外，化合物 35、39 和 43 对 αβnAChR 亚型表现出选择性部分激动剂活性。最后，在本文中，我们还报告了基于我们对该模板的综合结构活性关系（SAR）研究的关于 3,6-二氮杂双环[3.1.1]庚烷作为 nAChRs 配体的结论。
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