The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: The influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents

被引：15

作者：

Eibl, Christoph ^{[1
,2
]}

Tomassoli, Isabelle ^{[2
]}

Munoz, Lenka ^{[3
]}

Stokes, Clare ^{[4
]}

Papke, Roger L. ^{[4
]}

Guendisch, Daniela ^{[1
,2
]}

机构：

[1] Univ Bonn, Inst Pharmaceut, D-533121 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; PARTIAL AGONIST; AFFINITY; CYTISINE; CARBONYL; PHARMACOPHORE; VARENICLINE; SPARTEINE; BISPIDINE; SUBUNIT; ANALOGS;

D O I：

10.1016/j.bmc.2013.09.059

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 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 alpha 4 beta 2* were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for alpha 4 beta 2* 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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：7283 / 7308

页数：26

共 65 条

[1] Akireddy S. R, 2009, PCT Int. Appl., Patent No. [WO2009111550, 2009111550]
[2] N,N'-CARBONYLDIIMIDAZOLE, A NEW REAGENT FOR PEPTIDE SYNTHESIS
ANDERSON, GW
PAUL, R
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1958, 80 (16) : 4423 - 4423
[3] STRUCTURE AND ACTIVITY OF ACETYLCHOLINE
BEERS, WH
REICH, E
[J]. NATURE, 1970, 228 (5275) : 917 - &
[4] Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Blum, Angela P.
Lester, Henry A.
Dougherty, Dennis A.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (30) : 13206 - 13211
[5] Bunnelle W. H, 2000, PCT Int. Appl, Patent No. WO2000044755
[6] The Nicotinic Acetylcholine Receptor: The Founding Father of the Pentameric Ligand-gated Ion Channel Superfamily
Changeux, Jean-Pierre
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (48) : 40207 - 40215
[7] Varenicline:: An α4β2 nicotinic receptor partial agonist for smoking cessation
Coe, JW
Brooks, PR
Vetelino, MG
Wirtz, MC
Arnold, EP
Huang, JH
Sands, SB
Davis, TI
Lebel, LA
Fox, CB
Shrikhande, A
Heym, JH
Schaeffer, E
Rollema, H
Lu, Y
Mansbach, RS
Chambers, LK
Rovetti, CC
Schulz, DW
Tingley, FD
O'Neill, BT
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (10) : 3474 - 3477
[8] Catalytic aziridination of styrene with copper complexes of substituted 3,7-diazabicyclo[3.3.1]nonanones
Comba, P
Merz, M
Pritzkow, H
[J]. EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, 2003, (09) : 1711 - 1718
[9] Eibl C, 2009, THESIS U BONN GERMAN
[10] Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
Ghose, Arup K.
Herbertz, Torsten
Hudkins, Robert L.
Dorsey, Bruce D.
Mallamo, John P.
[J]. ACS CHEMICAL NEUROSCIENCE, 2012, 3 (01): : 50 - 68

← 1 2 3 4 5 6 7 →