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

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

doi:10.1021/jm701625v

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

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

21 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	51
Udgave nummer	23
Sider (fra-til)	7380-7395
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm701625v
Status	Udgivet - 2008

Emneord

Det tidligere Farmaceutiske Fakultet

Adgang til dokumentet

10.1021/jm701625v

Citationsformater

Novel acetylcholine and carbamoylcholine analogues : Development of a functionally selective a₄ß₂ nicotinic acetylcholine receptor agonist. / Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K. et al.

I: Journal of Medicinal Chemistry, Bind 51, Nr. 23, 2008, s. 7380-7395.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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 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.",

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AU - Liljefors, Tommy

AU - Frølund, Bente Flensborg

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N2 - 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.

AB - 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.

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