Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane

Bach, Tinna B.; Jensen, Anders A.; Petersen, Jette G.; Sørensen, Troels E.; Volpe, Serena Della; Li, Jun; Blaazer, Antoni R.; Muijlwijk‐Koezen, Jacqueline E. van; Balle, Thomas; Frølund, Bente

doi:10.1016/j.ejmech.2015.07.024

Cited by 3 publications

(2 citation statements)

References 50 publications

(77 reference statements)

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“…Drugs that selectively target a subpopulation of nAChRs within the brain’s nicotine reward pathway will have a great impact on the treatment of nicotine addiction. However, the design and development of novel nAChR orthosteric and allosteric ligands require: (1) an accurate mapping of anatomical distribution and delineation of functional contribution of various nAChRs; (2) precise understanding of the three dimensional structure of individual nAChR subtypes; (3) structural studies to illustrate drugs binding mode within the orthosteric binding site (e.g., Hansen et al, 2008 ; Bach et al, 2015 ). Such studies will provide structural information that may expand the chemical space in the development of novel partial agonists as a smoke cessation aids; and (4) structural studies to identify binding sites for nAChR PAMs (e.g., Seo et al, 2009 ; Olsen et al, 2013 ; Hamouda et al, 2015 ) and to understand the structural bases of PAM subtype selectivity.…”

Section: Discussionmentioning

confidence: 99%

Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation

Mohamed

Jayakar

Hamouda

2015

Front. Mol. Neurosci.

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Nicotine addiction, the result of tobacco use, leads to over six million premature deaths world-wide per year, a number that is expected to increase by a third within the next two decades. While more than half of smokers want and attempt to quit, only a small percentage of smokers are able to quit without pharmacological interventions. Therefore, over the past decades, researchers in academia and the pharmaceutical industry have focused their attention on the development of more effective smoking cessation therapies, which is now a growing 1.9 billion dollar market. Because the role of neuronal nicotinic acetylcholine receptors (nAChR) in nicotine addiction is well established, nAChR based therapeutics remain the leading strategy for smoking cessation. However, the development of neuronal nAChR drugs that are selective for a nAChR subpopulation is challenging, and only few neuronal nAChR drugs are clinically available. Among the many neuronal nAChR subtypes that have been identified in the brain, the α4β2 subtype is the most abundant and plays a critical role in nicotine addiction. Here, we review the role of neuronal nAChRs, especially the α4β2 subtype, in the development and treatment of nicotine addiction. We also compare available smoking cessation medications and other nAChR orthosteric and allosteric ligands that have been developed with emphasis on the difficulties faced in the development of clinically useful compounds with high nAChR subtype selectivity.

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Section: Discussionmentioning

confidence: 99%

Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation

Mohamed

Jayakar

Hamouda

2015

Front. Mol. Neurosci.

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“…It must be emphasized that in terms of modern ideas, such drugs should not cause addiction in human sand moreover, physical or psychological dependence, i.e., agonism with opioid receptors, is not acceptable in the mechanism of their analgesic action. Recently, with the purpose of searching for analgesics meeting such requirements, the agonists of neuronal nicotinic acetylcholine receptors ( n AChR) were actively studied [ 1 , 2 , 3 , 4 , 5 , 6 ]. Furthermore, they are of interest as potential agents to fight the manifestations of age-related neurodegeneration (Alzheimer’s disease [ 7 , 8 ], Parkinson’s disease [ 9 ], and various types of dementia [ 10 ]).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides

et al. 2016

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As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (1Н and 13С) spectra of the synthesized compounds are discussed. Using X-ray diffraction analysis, the ability of the compounds to form stable solvates with N,N-dimethylformamide has been shown on the example of 4-bromo-substituted derivative. It should be further studied to be considered in their crystallization. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick (tail immersion test) among halogen-substituted 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides, substances which are considerably superior to meloxicam and piroxicam by their analgesic activity have been found. They are of interest for further profound studies.

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Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists

Xue

Tang

et al. 2016

European Journal of Medicinal Chemistry

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Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane

Cited by 3 publications

References 50 publications

Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation

Orthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation

Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides

Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists

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