Novel acetylcholine and carbamoylcholine analogues: Development of a functionally selective a4ß2 nicotinic acetylcholine receptor agonist
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Novel acetylcholine and carbamoylcholine analogues : Development of a functionally selective a4ß2 nicotinic acetylcholine receptor agonist. / Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K.; Balle, Thomas; Liljefors, Tommy; Frølund, Bente Flensborg.
I: Journal of Medicinal Chemistry, Bind 51, Nr. 23, 2008, s. 7380-7395.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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
VL - 51
SP - 7380
EP - 7395
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -
ID: 9914377