ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors

Eur J Pharmacol. 2011 Jul 1;661(1-3):8-14. doi: 10.1016/j.ejphar.2011.04.028. Epub 2011 Apr 28.

Abstract

5-HT(6) receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT(6) receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT(6) receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT(6) receptors with good affinity (K(i)=28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT(2B), 5HT(1A), 5HT(7) receptors and adrenergic α receptors. ST1936 behaved as a full 5-HT(6) agonist on cloned cells and was able to increase Ca(2+) concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT(6) receptor antagonists, SB271046 and SB258585. The other 5-HT(6) receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT(6) receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cloning, Molecular
  • Cyclic AMP / metabolism*
  • Enzyme Activation / drug effects
  • Ethylamines / metabolism
  • Ethylamines / pharmacology*
  • Humans
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptors, Serotonin / genetics*
  • Receptors, Serotonin / metabolism*
  • Serotonin Receptor Agonists / pharmacology*
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology
  • Tryptamines / pharmacology

Substances

  • 2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine
  • Ethylamines
  • Indoles
  • N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Thiazoles
  • Tryptamines
  • serotonin 6 receptor
  • Cyclic AMP
  • Protein Kinases
  • Proto-Oncogene Proteins c-fyn
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Calcium