Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein

Bioorg Med Chem Lett. 2012 Feb 1;22(3):1448-54. doi: 10.1016/j.bmcl.2011.12.008. Epub 2011 Dec 9.

Abstract

Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benztropine / chemistry
  • Caprylates / chemistry*
  • Carrier Proteins / metabolism
  • Dicarboxylic Acids / chemistry*
  • Drug Design*
  • Ligands*
  • Models, Molecular
  • Protein Binding
  • Receptors, Nicotinic / chemistry*
  • Structure-Activity Relationship

Substances

  • Caprylates
  • Carrier Proteins
  • Dicarboxylic Acids
  • Ligands
  • Receptors, Nicotinic
  • Benztropine
  • suberic acid