title: Novel acetylcholine and carbamoylcholine analogues: development of a functionally selective alpha4beta2 nicotinic acetylcholine receptor agonist.
abstract: A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha4beta2 nAChR and pronounced selectivity for this subtype over alpha3beta4, alpha4beta4, and alpha7 nAChRs. The high nAChR activity of carbamoylcholine analogue 5d was found to reside in its R-enantiomer, a characteristic most likely true for all other compounds in the series. Interestingly, the pronounced alpha4beta2 selectivities exhibited by some of the compounds in the binding assays translated into functional selectivity. Compound 5a was a fairly potent partial alpha4beta2 nAChR agonist with negligible activities at the alpha3beta4 and alpha7 subtypes, thus being one of the few truly functionally selective alpha4beta2 nAChR agonists published to date. Ligand-protein docking experiments using homology models of the amino-terminal domains of alpha4beta2 and alpha3beta4 nAChRs identified residues Val111(beta2)/Ile113(beta4), Phe119(beta2)/Gln121(beta4), and Thr155(alpha4)/Ser150(alpha3) as possible key determinants of the alpha4beta2/alpha3beta4-selectivity displayed by the analogues.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, UniVersitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Camilla P
authors.initials: CP
authors.lastname: Hansen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Jeppe K
authors.initials: JK
authors.lastname: Christensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000109:Acetylcholine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002217:Carbachol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C403531:nicotinic receptor alpha4beta2; D002217:Carbachol; D000109:Acetylcholine