title: Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists.
abstract: In our search for selective agonists for the α(4)β(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α(4)β(2) over other nAChR subtypes, primarily due to impaired binding at β(4) containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α(4))(2)(β(2))(3) and (α(4))(3)(β(2))(2) receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α(4)-β(2) and α(4)-α(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α(4)-β(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Ussing
authors.forename: Camilla P
authors.initials: CP
authors.lastname: Hansen
authors.forename: Jette G
authors.initials: JG
authors.lastname: Petersen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Line A H
authors.initials: LA
authors.lastname: Rohde
authors.forename: Philip K
authors.initials: PK
authors.lastname: Ahring
authors.forename: Elsebet Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D008195:Lymnaea; D008564:Membrane Potentials; D008958:Models, Molecular; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2