The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

被引：19
|
作者：
Eibl, Christoph [1 ,2 ]
Munoz, Lenka [1 ,3 ]
Tomassoli, Isabelle [2 ]
Stokes, Clare [4 ]
Papke, Roger L. [4 ]
Guendisch, Daniela [1 ,2 ]
机构：
[1] Univ Bonn, Inst Pharmaceut, D-53121 Bonn, Germany
[2] Univ Hawaii, Daniel K Inouye Coll Pharm, Dept Pharmaceut Sci, Hilo, HI 96720 USA
[3] Univ Sydney, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2006, Australia
[4] Univ Florida, Coll Med, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 23期
基金：
美国国家卫生研究院; 美国国家科学基金会;
关键词：
3,7-Diazabicyclo[3.3.1]nonane; Bispidine; Nicotinic acetylcholine receptor nAChR; Structure-activity relationship; Cytisine; CYTISINE; AFFINITY; AGONISTS;
D O I：
10.1016/j.bmc.2013.09.060
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 alpha 4 beta 2* nAChR. Compounds 15, 25, and 47 with K-i values of about 1 nM displayed the highest affinities for alpha 4 beta 2* nAChR. All evaluated compounds are partial agonists or antagonists at alpha 4 beta 2*, with reduced or no effects on alpha 3 beta 4* with the exception of compound 15 (agonist), and reduced or no effect at alpha 7 and muscle subtypes. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码：7309 / 7329
页数：21
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