Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores

Bioorg Med Chem. 2016 Aug 15;24(16):3671-9. doi: 10.1016/j.bmc.2016.06.011. Epub 2016 Jun 4.


Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.

Keywords: Antipsychotic; CNS receptor; Dopamine receptor ligands; Multi-receptor targeting; Pharmacophore.

MeSH terms

  • Animals
  • Dopamine Agents / metabolism
  • Humans
  • Ligands
  • Proton Magnetic Resonance Spectroscopy
  • Receptors, Dopamine D2 / metabolism*


  • Dopamine Agents
  • Ligands
  • Receptors, Dopamine D2