Conformationally-flexible benzamide analogues as dopamine D3 and sigma 2 receptor ligands

Bioorg Med Chem Lett. 2004 Jan 5;14(1):195-202. doi: 10.1016/j.bmcl.2003.09.083.


A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D2, D3 and D4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K(i) value=2nM) and moderate selectivity (30-fold) for D3 compared to D2 receptors. In addition, this series of compounds were also tested for affinity at sigma1 and sigma2 receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for sigma2 versus sigma1 receptors. Consequently, these novel compounds may be useful for characterizing the functional role of sigma2 receptors and for imaging the sigma2 receptor status of tumors in vivo with PET.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzamides / chemistry*
  • Benzamides / metabolism*
  • Brain / metabolism
  • Cell Line
  • Guinea Pigs
  • Humans
  • Ligands
  • Molecular Conformation
  • Rats
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3
  • Receptors, sigma / metabolism*
  • Structure-Activity Relationship


  • Benzamides
  • DRD3 protein, human
  • Drd3 protein, rat
  • Ligands
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, sigma
  • sigma-2 receptor