Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 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):7309-29. doi: 10.1016/j.bmc.2013.09.060. Epub 2013 Oct 5.
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.
已合成了基于 3,7-二氮杂双环[3.3.1]壬烷（比斯的定）的烟碱型乙酰胆碱受体（nAChR）配体，并对其与 nAChR 的相互作用进行了评估。在氢键受体（HBA）部分和各种取代的（杂）芳基部分之间，掺入了不同的间隔基模体。带有间隔基模体的比斯的定羧酰胺通常表现出对 α4β2(∗) nAChR 的高亲和力和选择性，亲和力在低纳摩尔范围内。Ki 值约为 1 nM 的化合物 15、25 和 47 对 α4β2(∗) nAChR 表现出最高的亲和力。所有评价的化合物都是 α4β2(∗) 的部分激动剂或拮抗剂，除了化合物 15（激动剂）之外，对 α3β4(∗) 的作用减弱或没有，对 α7 和肌肉亚型的作用也减弱或没有。
