Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist

J Med Chem. 2003 Mar 27;46(7):1273-6. doi: 10.1021/jm021085c.

Abstract

A small series of aryl pyridyl sulfones has been prepared and investigated for its 5-HT(6) receptor binding properties. Thereof, pyrrolidinyl derivative 11 proved to be a very potent (pK(i) 9) and selective 5-HT(6) receptor antagonist. By means of in vivo microdialysis in the frontal cortex and a passive avoidance paradigm, where 11 reversed a scopolamine induced retention deficit, a functional correlation between 5-HT(6) receptors and cholinergic neurotransmission could be shown, supporting the therapeutic potential of 5-HT(6) receptors in the treatment of cognitive deficits.

MeSH terms

  • Acetylcholine / metabolism*
  • Administration, Oral
  • Animals
  • Avoidance Learning / drug effects
  • Biological Availability
  • Blood-Brain Barrier
  • Cell Line
  • Frontal Lobe / drug effects*
  • Frontal Lobe / metabolism
  • Half-Life
  • Humans
  • In Vitro Techniques
  • Injections, Intravenous
  • Microdialysis
  • Microsomes, Liver / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / physiology
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Tissue Distribution

Substances

  • 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Sulfones
  • serotonin 6 receptor
  • Acetylcholine