Design, synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives

Bioorg Med Chem Lett. 2019 Nov 1;29(21):126667. doi: 10.1016/j.bmcl.2019.126667. Epub 2019 Sep 3.

Abstract

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM - antagonist mode) and D2 (compound 15, Ki = 7 nM - antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.

Keywords: Depression; Dopamine receptors; Organic synthesis; Serotonin receptors; Solvent-free.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / pharmacology
  • Binding Sites
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / pharmacology
  • Drug Evaluation, Preclinical
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemistry
  • Protein Binding
  • Receptors, Dopamine / metabolism*
  • Receptors, Serotonin / metabolism*
  • Saccharin / chemistry*
  • Serotonin
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / pharmacology
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antidepressive Agents
  • Dopamine Antagonists
  • Ligands
  • Piperazines
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin
  • Saccharin