Ussing_2013_J.Med.Chem_56_940

Reference

Title : Synthesis, pharmacology, and biostructural characterization of novel alpha4beta2 nicotinic acetylcholine receptor agonists - Ussing_2013_J.Med.Chem_56_940
Author(s) : Ussing CA , Hansen CP , Petersen JG , Jensen AA , Rohde LA , Ahring PK , Nielsen EO , Kastrup JS , Gajhede M , Frolund B , Balle T
Ref : Journal of Medicinal Chemistry , 56 :940 , 2013
Abstract :

In 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.

PubMedSearch : Ussing_2013_J.Med.Chem_56_940
PubMedID: 23256554

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Citations formats

Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EO, Kastrup JS, Gajhede M, Frolund B, Balle T (2013)
Synthesis, pharmacology, and biostructural characterization of novel alpha4beta2 nicotinic acetylcholine receptor agonists
Journal of Medicinal Chemistry 56 :940

Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EO, Kastrup JS, Gajhede M, Frolund B, Balle T (2013)
Journal of Medicinal Chemistry 56 :940