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
Copyright © 2015 Elsevier Masson SAS. All rights reserved..
X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:102 |
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| Enthalten in: |
European journal of medicinal chemistry - 102(2015) vom: 18. Sept., Seite 425-44 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bach, Tinna B [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.06.2016 Date Revised 12.09.2015 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2015.07.024 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM252104536 |
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| 100 | 1 | |a Bach, Tinna B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
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| 500 | |a Date Completed 14.06.2016 | ||
| 500 | |a Date Revised 12.09.2015 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2015 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Ac-AChBP | |
| 650 | 4 | |a DMABC analogs | |
| 650 | 4 | |a Lobeline | |
| 650 | 4 | |a Ls-AChBP | |
| 650 | 4 | |a Structure–activity studies | |
| 650 | 4 | |a nACh receptor agonists | |
| 650 | 7 | |a Azepines |2 NLM | |
| 650 | 7 | |a Carbamates |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Receptors, Nicotinic |2 NLM | |
| 650 | 7 | |a nicotinic receptor alpha4beta2 |2 NLM | |
| 700 | 1 | |a Jensen, Anders A |e verfasserin |4 aut | |
| 700 | 1 | |a Petersen, Jette G |e verfasserin |4 aut | |
| 700 | 1 | |a Sørensen, Troels E |e verfasserin |4 aut | |
| 700 | 1 | |a Della Volpe, Serena |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Blaazer, Antoni R |e verfasserin |4 aut | |
| 700 | 1 | |a van Muijlwijk-Koezen, Jacqueline E |e verfasserin |4 aut | |
| 700 | 1 | |a Balle, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Frølund, Bente |e verfasserin |4 aut | |
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