title: Synthesis and structure--activity relationship in a class of indolebutylpiperazines as dual 5-HT(1A) receptor agonists and serotonin reuptake inhibitors.
abstract: Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT(1A) receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT(1A) receptor affinity and to suppress D(2) receptor binding. 5-[4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl]benzofuran-2-carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 1.1 nM] with subnanomolar 5-HT(1A) affinity [IC(50) = 0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI = 0.5 nM] showing a great selectivity to other GPCRs (e.g., D(2), IC(50) = 666 nM).
authors.affiliation: Preclinical Pharmaceutical Research, Merck KGaA, Frankfurter Strasse 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: Rolf
authors.initials: R
authors.lastname: Gericke
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: Soheila
authors.initials: S
authors.lastname: Anzali
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Seyfried
authors.forename: Hartmut E
authors.initials: HE
authors.lastname: Greiner
authors.forename: Christoph
authors.initials: C
authors.lastname: Van Amsterdam
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D000077489:Piperazine; D010879:Piperazines; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C030374:indole