Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-533121 Bonn, Germany; Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
Bioorg Med Chem. 2013 Dec 1;21(23):7283-308. doi: 10.1016/j.bmc.2013.09.059. Epub 2013 Oct 5.
3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.
3,7-二氮杂双环[3.3.1]壬烷是一种与烟碱型乙酰胆碱受体（nAChRs）相互作用的天然支架。当 3,7-二氮杂双环[3.3.1]壬烷支架的一个氮原子被引入具有氢键受体（HBA）功能的羧酰胺基序时，得到了对α4β2（）具有更高亲和力和亚型选择性的化合物。HBA 系统（羧酰胺、磺酰胺、脲）的性质对 nAChR 相互作用有很强的影响。具有高亲和力的α4β2（）配体具有小的烷基链、小的未取代杂芳基或对位取代的苯环系统以及羧酰胺基团。对表达各种 nAChR 亚型的非洲爪蟾卵母细胞进行的选定 3,7-二氮杂双环[3.3.1]壬烷衍生物的电生理反应显示出不同的激活谱。具有最强激动作用的化合物具有小的烷基基团，而对于芳基取代基则观察到部分激动剂/拮抗剂作用的转变。
