title: ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors.
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.
authors.affiliation: Sigma-tau Industrie Farmaceutiche Riunite S.p.A., Pomezia, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Fabio
authors.initials: F
authors.lastname: Bordi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Hyung-Mun
authors.initials: HM
authors.lastname: Yun
authors.forename: Bo-Hye
authors.initials: BH
authors.lastname: Im
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
mesh_terms: D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005021:Ethylamines / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
chemical_list: C558115:2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine; D005021:Ethylamines; D007211:Indoles; C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014363:Tryptamines; C097216:serotonin 6 receptor; D000242:Cyclic AMP; D011494:Protein Kinases; D051076:Proto-Oncogene Proteins c-fyn; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium