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 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	23
Pages (from-to)	7380-7395
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm701625v
Publication status	Published - 2008

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/jm701625v

Cite this

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.

In: Journal of Medicinal Chemistry, Vol. 51, No. 23, 2008, p. 7380-7395.

Research output: Contribution to journal › Journal article › Research › peer-review

@article{92191d60e95e11ddbf70000ea68e967b,

title = "Novel acetylcholine and carbamoylcholine analogues: Development of a functionally selective a4{\ss}2 nicotinic acetylcholine receptor agonist",

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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Hansen, {Camilla Petrycer} and Jensen, {Anders Asbj{\o}rn} and Christensen, {Jeppe K.} and Thomas Balle and Tommy Liljefors and Fr{\o}lund, {Bente Flensborg}",

year = "2008",

doi = "10.1021/jm701625v",

language = "English",

volume = "51",

pages = "7380--7395",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "23",

}

TY - JOUR

T1 - Novel acetylcholine and carbamoylcholine analogues

T2 - Development of a functionally selective a4ß2 nicotinic acetylcholine receptor agonist

AU - Hansen, Camilla Petrycer

AU - Jensen, Anders Asbjørn

AU - Christensen, Jeppe K.

AU - Balle, Thomas

AU - Liljefors, Tommy

AU - Frølund, Bente Flensborg

PY - 2008

Y1 - 2008

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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm701625v

DO - 10.1021/jm701625v

M3 - Journal article

C2 - 18989912

SN - 0022-2623

VL - 51

SP - 7380

EP - 7395

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -