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

Abstract

5-HT6 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-HT6 receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT6 receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT6 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 alpha receptors. ST1936 behaved as a full 5-HT6 agonist on cloned cells and was able to increase Ca2+ 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-HT6 receptor antagonists, SB271046 and SB258585. The other 5-HT6 receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT6 receptor-dependent signal pathways, such as cAMP. Fyn and ERK1/2 kinase, as specific agonists. (C) 2011 Elsevier B.V. All rights reserved.