Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT1A receptor agonists for CNS disorders and neuropathic pain

Future Med Chem. 2018 Sep 1;10(18):2137-2154. doi: 10.4155/fmc-2018-0107. Epub 2018 Jul 25.

Abstract

Aim: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control.

Methodology: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds.

Results & conclusion: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.

Keywords: 5-HT1A receptor agonist; antinociceptive activity; neuroprotection; α1-adrenoceptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Central Nervous System Diseases / drug therapy*
  • Central Nervous System Diseases / metabolism
  • Dioxolanes / chemical synthesis
  • Dioxolanes / chemistry*
  • Dioxolanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship

Substances

  • Dioxolanes
  • Neuroprotective Agents
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • formal glycol