Structural highlights
Function[ACHP_LYMST] Binds to acetylcholine. Modulates neuronal synaptic transmission. Publication Abstract from PubMedIn our search for selective agonists for the alpha(4)beta(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 alpha(4)beta(2) over other nAChR subtypes, primarily due to impaired binding at beta(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 (alpha(4))(2)(beta(2))(3) and (alpha(4))(3)(beta(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 alpha(4)-beta(2) and alpha(4)-alpha(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 alpha(4)-beta(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences. Synthesis, Pharmacology, and Biostructural Characterization of Novel alpha(4)beta(2) Nicotinic Acetylcholine Receptor Agonists.,Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EO, Kastrup JS, Gajhede M, Frolund B, Balle T J Med Chem. 2013 Feb 14;56(3):940-51. doi: 10.1021/jm301409f. Epub 2013 Jan 22. PMID:23256554[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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