title: 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.
abstract: 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.
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Tinna B
authors: TB
authors: Bach
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Anders A
authors: AA
authors: Jensen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Jette G
authors: JG
authors: Petersen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors: Troels E
authors: TE
authors: Sørensen
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Serena
authors: S
authors: Della Volpe
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors: Jun
authors: J
authors: Liu
authors: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
authors: Antoni R
authors: AR
authors: Blaazer
authors: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
authors: Jacqueline E
authors: JE
authors: van Muijlwijk-Koezen
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: thomas.balle@sydney.edu.au.
authors: Thomas
authors: T
authors: Balle
authors: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: bfr@sund.ku.dk.
authors: Bente
authors: B
authors: Frølund
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D002219:Carbamates; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2
keywords: Ac-AChBP; DMABC analogs; Lobeline; Ls-AChBP; Structure–activity studies; nACh receptor agonists