Synthesis, pharmacology and biostructural characterization of novel a4ß2 nicotinic acetylcholine receptor agonists

Christine A. Ussing; Camilla Petrycer Hansen; Jette Gellert Petersen; Anders A. Jensen; Line A.H.  Rohde; Philip K. Ahring; Elisabeth Ø.  Nielsen; Jette Sandholm Kastrup; Michael Gajhede; Bente Frølund; Thomas Balle

doi:10.1021/jm301409f

Synthesis, pharmacology and biostructural characterization of novel a4ß2 nicotinic acetylcholine receptor agonists

Christine A. Ussing, Camilla Petrycer Hansen, Jette Gellert Petersen, Anders A. Jensen, Line A.H. Rohde, Philip K. Ahring, Elisabeth Ø. Nielsen, Jette Sandholm Kastrup, Michael Gajhede, Bente Frølund, Thomas Balle

12 Citations (Scopus)

Abstract

In our search for selective agonists for the α₄β ₂ subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α₄β₂ over other nAChR subtypes, primarily due to impaired binding at β₄ containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α₄)₂(β₂) ₃ and (α₄)₃(β₂) ₂ receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α₄-β₂ and α₄- α₄ binding sites, while the close analogue N,N-dimethyl-4-(1,4- dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α₄-β₂ binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.

Original language	Danish
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	3
Pages (from-to)	940-951
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm301409f
Publication status	Published - 14 Feb 2013

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10.1021/jm301409f

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Ussing, C. A., Hansen, C. P., Petersen, J. G., Jensen, A. A., Rohde, L. A. H., Ahring, P. K., Nielsen, E. Ø., Kastrup, J. S., Gajhede, M., Frølund, B., & Balle, T. (2013). Synthesis, pharmacology and biostructural characterization of novel a4ß2 nicotinic acetylcholine receptor agonists. Journal of Medicinal Chemistry, 56(3), 940-951. https://doi.org/10.1021/jm301409f

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abstract = "In our search for selective agonists for the α4β 2 subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α4β2 over other nAChR subtypes, primarily due to impaired binding at β4 containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α4)2(β2) 3 and (α4)3(β2) 2 receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α4-β2 and α4- α4 binding sites, while the close analogue N,N-dimethyl-4-(1,4- dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α4-β2 binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.",

author = "Ussing, {Christine A.} and Hansen, {Camilla Petrycer} and Petersen, {Jette Gellert} and Jensen, {Anders A.} and Rohde, {Line A.H.} and Ahring, {Philip K.} and Nielsen, {Elisabeth {\O}.} and Kastrup, {Jette Sandholm} and Michael Gajhede and Bente Fr{\o}lund and Thomas Balle",

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T1 - Synthesis, pharmacology and biostructural characterization of novel a4ß2 nicotinic acetylcholine receptor agonists

AU - Ussing, Christine A.

AU - Hansen, Camilla Petrycer

AU - Petersen, Jette Gellert

AU - Jensen, Anders A.

AU - Rohde, Line A.H.

AU - Ahring, Philip K.

AU - Nielsen, Elisabeth Ø.

AU - Kastrup, Jette Sandholm

AU - Gajhede, Michael

AU - Frølund, Bente

AU - Balle, Thomas

PY - 2013/2/14

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N2 - In our search for selective agonists for the α4β 2 subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α4β2 over other nAChR subtypes, primarily due to impaired binding at β4 containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α4)2(β2) 3 and (α4)3(β2) 2 receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α4-β2 and α4- α4 binding sites, while the close analogue N,N-dimethyl-4-(1,4- dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α4-β2 binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.

AB - In our search for selective agonists for the α4β 2 subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α4β2 over other nAChR subtypes, primarily due to impaired binding at β4 containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α4)2(β2) 3 and (α4)3(β2) 2 receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α4-β2 and α4- α4 binding sites, while the close analogue N,N-dimethyl-4-(1,4- dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α4-β2 binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.

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