title: Dual 5-HT1A agonists and 5-HT re-uptake inhibitors by combination of indole-butyl-amine and chromenonyl-piperazine structural elements in a single molecular entity.
abstract: The dual serotonin (5-HT) re-uptake inhibitor and 5-HT(1A) receptor agonist vilazodone was found to increase central serotonin levels in rat brain. In the course of structural modifications of vilazodone 3-[4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl]-1H-indole-5-carbonitrile 8i and its fluorine analogue 6-[4-[4-(5-fluor-3-indolyl)-butyl]-1-piperazinyl]-2H-1-benzopyran-2-one have been identified. These unsubstituted chromenones are equally potent at the 5-HT(1A) receptor and 5-HT transporter. The implementation of nitrogen functionalities in position 3 of the chromenones resulted in compounds acting as agonists at the 5-HT(1A) receptor and as 5-HT re-uptake inhibitors like vilazodone. Ex vivo 5-HT re-uptake inhibition and in vitro 5-HT agonism were determined in the PCA- and GTPgammaS-assay, respectively. The potential of these chromenones to increase central 5-HT levels was measured in microdialysis studies and especially the derivatives 3-[4-[4-(3-amino-2-oxo-2H-chromen-6-yl)-piperazin-1-yl]-butyl]-1H-indole-5-carbonitrile 8f, ethyl (6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-carbamate 8h and N-(6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-acetamide 8k give rise to rapid development of increased serotonin levels in rat brain cortex, lasting longer than 3h.
authors.affiliation: Preclinical Pharmaceutical Research, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany. timo.heinrich@merck.de
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.forename: Henning
authors.initials: H
authors.lastname: Böttcher
authors.forename: Kai
authors.initials: K
authors.lastname: Schiemann
authors.forename: Günter
authors.initials: G
authors.lastname: Hölzemann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: Christoph
authors.initials: C
authors.lastname: van Amsterdam
authors.forename: Hartmut E
authors.initials: HE
authors.lastname: Greiner
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Seyfried
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002082:Butylamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000069503:Vilazodone Hydrochloride
chemical_list: D001572:Benzofurans; D001578:Benzopyrans; D002082:Butylamines; D004338:Drug Combinations; D007211:Indoles; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069503:Vilazodone Hydrochloride