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Bioorg Med Chem
2013 Dec 01;2123:7283-308. doi: 10.1016/j.bmc.2013.09.059.
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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.
Eibl C, Tomassoli I, Munoz L, Stokes C, Papke RL, Gündisch D.
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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.
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Beers,
Structure and activity of acetylcholine.
1970, Pubmed
Beers,
Structure and activity of acetylcholine.
1970,
Pubmed Blum,
Nicotinic pharmacophore: the pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH.
2010,
Pubmed
,
Xenbase Changeux,
The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily.
2012,
Pubmed Coe,
Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
2005,
Pubmed
,
Xenbase Ghose,
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery.
2012,
Pubmed Glennon,
alpha4beta2 nACh receptor pharmacophore models.
2004,
Pubmed Gnädisch,
High affinity binding of [3H]epibatidine to rat brain membranes.
1999,
Pubmed Gotti,
Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement.
2010,
Pubmed Gündisch,
Nicotinic acetylcholine receptor ligands, a patent review (2006-2011).
2011,
Pubmed Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase Hogg,
Nicotinic acetylcholine receptors: from structure to brain function.
2003,
Pubmed Hurst,
Nicotinic acetylcholine receptors: from basic science to therapeutics.
2013,
Pubmed Imming,
Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands.
2001,
Pubmed Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed Kombo,
Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with α4β2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes.
2013,
Pubmed Le Novère,
Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells.
1995,
Pubmed Lipinski,
Lead- and drug-like compounds: the rule-of-five revolution.
2004,
Pubmed Mazurov,
Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor.
2013,
Pubmed Mazurov,
Discovery of 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a novel highly selective α4β2 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders.
2012,
Pubmed Mineur,
Cytisine-based nicotinic partial agonists as novel antidepressant compounds.
2009,
Pubmed
,
Xenbase Mineur,
Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice.
2007,
Pubmed Mukhin,
5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors.
2000,
Pubmed O'Donnell,
Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates--subtype selective, high affinity alpha7 nicotinic acetylcholine receptor agonists.
2009,
Pubmed Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase Peng,
Differential modulation of brain nicotinic acetylcholine receptor function by cytisine, varenicline, and two novel bispidine compounds: emergent properties of a hybrid molecule.
2013,
Pubmed
,
Xenbase Pérez,
Cytisine: a natural product lead for the development of drugs acting at nicotinic acetylcholine receptors.
2012,
Pubmed Picciotto,
Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior.
2012,
Pubmed Picciotto,
Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.
1998,
Pubmed Quik,
Role of α6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders.
2011,
Pubmed Rollema,
Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect.
2009,
Pubmed Romanelli,
Central nicotinic receptors: structure, function, ligands, and therapeutic potential.
2007,
Pubmed Ruenitz,
Antiarrhythmic activity of some N-alkylbispidinebenzamides.
1979,
Pubmed Ruenitz,
Analogues of sparteine. 5. Antiarrhythmic activity of selected N,N'-disubstituted bispidines.
1977,
Pubmed Sheridan,
The ensemble approach to distance geometry: application to the nicotinic pharmacophore.
1986,
Pubmed Siener,
Synthesis and opioid receptor affinity of a series of 2, 4-diaryl-substituted 3,7-diazabicylononanones.
2000,
Pubmed Smissman,
Analogues of sparteine. II. Synthesis of N-monoalkylbispidines and N,N'-dialkylbispidines.
1976,
Pubmed Stead,
Concise synthesis of (+/-)-cytisine via lithiation of N-Boc-bispidine.
2005,
Pubmed Tønder,
Agonists at the alpha4beta2 nicotinic acetylcholine receptors: structure-activity relationships and molecular modelling.
2001,
Pubmed Tosco,
Complementary three-dimensional quantitative structure-activity relationship modeling of binding affinity and functional potency: a study on alpha4beta2 nicotinic ligands.
2009,
Pubmed
