title: Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein.
abstract: Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes.
authors.affiliation: Leiden/Amsterdam Center of Drug Research, Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands.
authors.forename: Ewald
authors.initials: E
authors.lastname: Edink
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.forename: Chimed
authors.initials: C
authors.lastname: Jansen
authors.forename: René
authors.initials: R
authors.lastname: van Elk
authors.forename: Obbe
authors.initials: O
authors.lastname: Zuiderveld
authors.forename: Frans J J
authors.initials: FJ
authors.lastname: de Kanter
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: van Muijlwijk-Koezen
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D001590:Benztropine / Q000737:chemistry; D002210:Caprylates / Q000737:chemistry*; D002352:Carrier Proteins / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000737:chemistry*; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D002210:Caprylates; D002352:Carrier Proteins; D003998:Dicarboxylic Acids; D008024:Ligands; D011978:Receptors, Nicotinic; D001590:Benztropine; C005738:suberic acid