title: Design, synthesis and binding affinity of acetylcholine carbamoyl analogues.
abstract: A series of acetylcholine carbamoyl analogues, cyclised at the carbamate moiety or at the cationic head or at both, were tested for binding affinity at muscarinic and neuronal nicotinic receptors (nAChRs). While no muscarinic affinity was found, submicromolar Ki values, similar to that of carbachol, were measured at α4β2 nAChRs for the enantiomers of 5-dimethylaminomethyl- and 5-trimethylammoniomethyl-2-oxazolidinone, 2 and 2a, and for (S)-N-methylprolinol carbamate (S)-3. Methylation of oxazolidinone nitrogen of 2 and 2a and of N-methylprolinol nitrogen of (S)-3 and, even more, hybridization of cyclic carbamate substructure (oxazolidinone) with cyclic cationic head (N-methylpyrrolidine) markedly lower the nicotinic affinity. Docking results were consistent with SAR analysis highlighting the interaction capabilities of (R)-2a and (S)-3 and the negative effect of intracyclic nitrogen methylation and of double cyclisation.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.forename: Matteo
authors.initials: M
authors.lastname: Binda
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.forename: Rossana
authors.initials: R
authors.lastname: Ferrara
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
mesh_terms: D000109:Acetylcholine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002217:Carbachol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D008024:Ligands; D002217:Carbachol; D000109:Acetylcholine
keywords: Affinity; Carbachol; Carbamoyl; Ligand; Oxazolidinone; nAChR