title: Partial agonist efficacy of EMD386088, a 5-HT6 receptor ligand, in functional in vitro assays.
abstract: BACKGROUND
  Over recent years, the 5-hydroxytryptamine6 (5-HT6) receptor has emerged as a promising molecular target which interacts with several central nervous system acting drugs. In animal models, both agonists and antagonists of this receptor exhibit equivalent potency and efficacy as potential antidepressants, anxiolytics and anti-obesity or anti-dementia drugs. EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) has been described as a high affinity 5-HT6 receptor ligand with a full agonist activity and with moderate affinity for 5-HT3 sites.
  
  
  METHODS
  We have extended these data by broadening its profile for other, not yet tested, monoaminergic, GABA(A), opioid μ receptors and serotonin transporter (SERT) and we have conducted functional in vitro assays; i.e., measurement of cAMP by homogeneous TR-FRET immunoassay and HTRF method made by CEREP as well as aequorin-based calcium flux assay.
  
  
  RESULTS
  In two in vitro models based on cAMP formation, maximal efficacy values for EMD386088 were 65 and 31%, for in house and CEREP experiments, respectively. In a model based on calcium response, the studied compound showed 46% of maximal serotonin (5-HT) signal. EMD386088 antagonizes 5-HT response in increasing concentrations from 10(-9) to 10(-6) M.
  
  
  CONCLUSIONS
  The present in vitro findings confirm that EMD386088 is a selective 5-HT6 receptor ligand with moderate affinity for 5-HT3 sites only and it behaves as a potent partial agonist of 5-HT6 receptor with varying levels of agonist intrinsic activity, depending on a method employed. In view of these results, caution is recommended in the interpretation of pharmacological in vivo studies with EMD386088.
authors.affiliation: Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. awesolowska@cm-uj.krakow.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.forename: Barbara
authors.initials: B
authors.lastname: Nawieśniak
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.forename: Monika
authors.initials: M
authors.lastname: Marcinkowska
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D054333:Drug Partial Agonism; D006801:Humans; D007211:Indoles / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: C534240:5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor; D012701:Serotonin; D000242:Cyclic AMP; D002118:Calcium