The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
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DOI：
10.1016/j.bmc.2013.09.060
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Gündisch D
中科院分区：
文献类型：
--
作者：
Eibl C;Munoz L;Tomassoli I;Stokes C;Papke RL;Gündisch D
合成了基于3，7-二氮杂双环[3.3.1]壬烷（bispidine）的烟碱乙酰胆碱受体（nAChR）配体并评价了nAChR相互作用。在氢键受体（HBA）部分和各种取代的（杂）芳基部分之间引入不同的间隔基序。带有间隔基序的双吡啶甲酰胺通常在低纳摩尔范围内显示出高亲和力和对α4β2* nAChR的选择性。Ki值约为1 nM的化合物15、25和47显示出对α4β2* nAChR的最高亲和力。所有评价的化合物均为α4β2* 的部分激动剂或拮抗剂，除化合物15（激动剂）外，对α3β4* 的作用降低或无作用，对α7和肌肉亚型的作用降低或无作用。
3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2* nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2* nAChR. All evaluated compounds are partial agonists or antagonists at α4β2*, with reduced or no effects on α3β4* with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.