3ZDH

Crystal structure of Ls-AChBP complexed with carbamoylcholine analogue N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine

Summary for 3ZDH

• Entry DOI: 10.2210/pdb3zdh/pdb
• Related: 3ZDG
• Descriptor: ACETYLCHOLINE BINDING PROTEIN, (2R)-N,N-dimethyl-4-(1-methylimidazol-2-yl)oxy-butan-2-amine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: acetylcholine-binding protein
• Biological source: LYMNAEA STAGNALIS (GREAT POND SNAIL)
• Cellular location: Secreted: P58154
• Total number of polymer chains: 10
• Total formula weight: 241232.54

Authors

Ussing, C.A.,Hansen, C.P.,Petersen, J.G.,Jensen, A.A.,Rohde, L.A.H.,Ahring, P.K.,Nielsen, E.O.,Kastrup, J.S.,Gajhede, M.,Frolund, B.,Balle, T. (deposition date: 2012-11-26, release date: 2013-02-20, Last modification date: 2024-11-13)

Primary citation

Ussing, C.A.,Hansen, C.P.,Petersen, J.G.,Jensen, A.A.,Rohde, L.A.H.,Ahring, P.K.,Nielsen, E.O.,Kastrup, J.S.,Gajhede, M.,Frolund, B.,Balle, T.
Synthesis, Pharmacology, and Biostructural Characterization of Novel Alpha(4)Beta(2) Nicotinic Acetylcholine Receptor Agonists.
J.Med.Chem., 56:940-, 2013

PubMed Abstract: In our search for selective agonists for the α(4)β(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 α(4)β(2) over other nAChR subtypes, primarily due to impaired binding at β(4) 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 (α(4))(2)(β(2))(3) and (α(4))(3)(β(2))(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 α(4)-β(2) and α(4)-α(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α(4)-β(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.

PubMed: 23256554
DOI: 10.1021/JM301409F

Experimental method

X-RAY DIFFRACTION (2.195 Å)