title: Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations.
abstract: Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.
authors: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Mario
authors: M
authors: de la Fuente Revenga
authors: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors: Thomas
authors: T
authors: Balle
authors: University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Anders A
authors: AA
authors: Jensen
authors: University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: bfr@sund.ku.dk.
authors: Bente
authors: B
authors: Frølund
mesh_terms: D002217:Carbachol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D002217:Carbachol
keywords: Acetylcholine; Agonist; Conformational restriction; Docking; Nicotinic acetylcholine receptor