Synthesis, Pharmacology, and Biostructural Characterization of Novel α4β2 Nicotinic Acetylcholine Receptor Agonists

J Med Chem. 2013 Feb 14;56(3):940-51. doi: 10.1021/jm301409f. Epub 2013 Jan 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Lymnaea
  • Membrane Potentials
  • Models, Molecular
  • Nicotinic Antagonists / chemical synthesis*
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology*
  • Nuclear Magnetic Resonance, Biomolecular
  • Radioligand Assay
  • Receptors, Nicotinic / drug effects*
  • Xenopus laevis

Substances

  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2