Novel acetylcholine and carbamoylcholine analogues: Development of a functionally selective a4ß2 nicotinic acetylcholine receptor agonist

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Camilla Petrycer Hansen, Anders Asbjørn Jensen, Jeppe K. Christensen, Thomas Balle, Tommy Liljefors, Bente Flensborg Frølund

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 alpha 4beta 2 nAChR and pronounced selectivity for this subtype over alpha 3beta 4, alpha 4beta 4, and alpha 7 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 alpha 4beta 2 selectivities exhibited by some of the compounds in the binding assays translated into functional selectivity. Compound 5a was a fairly potent partial alpha 4beta 2 nAChR agonist with negligible activities at the alpha 3beta 4 and alpha 7 subtypes, thus being one of the few truly functionally selective alpha 4beta 2 nAChR agonists published to date. Ligand-protein docking experiments using homology models of the amino-terminal domains of alpha 4beta 2 and alpha 3beta 4 nAChRs identified residues Val111(beta 2)/Ile113(beta 4), Phe119(beta 2)/Gln121(beta 4), and Thr155(alpha 4)/Ser150(alpha 3) as possible key determinants of the alpha 4beta 2/alpha 3beta 4-selectivity displayed by the analogues.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number23
Pages (from-to)7380-7395
Publication statusPublished - 2008

ID: 9914377