The twin drug approach for novel nicotinic acetylcholine receptor ligands

Bioorg Med Chem. 2015 Aug 1;23(15):4375-4389. doi: 10.1016/j.bmc.2015.06.034. Epub 2015 Jun 20.


The association of two pharmacophoric entities generates so-called 'twin drugs' or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with α4β2(∗) nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N,N-dimethyl-2-(pyridin-3-yloxy)ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the 'twin' compound. 'Twin' compounds with identical or non-identical entities using the 'no linker mode' or 'overlap' mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the α4β2(∗) nAChR subtype (Ki=0.188 nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono- or difluoro-phenyls. The 'twin drug' approach proved to provide compounds with high affinity and subtype selectivity for α4β2(∗) nAChRs.

Keywords: 3D QSAR pharmacophore; Nicotinic acetylcholine receptor; Structure–activity relationship; Twin drugs; nAChR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dimerization
  • Drug Design
  • Ligands
  • Mice
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry*
  • Quantitative Structure-Activity Relationship
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism


  • Ligands
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2