title: Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition.
abstract: A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.
authors.affiliation: Solvay Pharmaceuticals Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. pieter.smid@solvay.com
authors.forename: Pieter
authors.initials: P
authors.lastname: Smid
authors.forename: Hein K A C
authors.initials: HK
authors.lastname: Coolen
authors.forename: Hiskias G
authors.initials: HG
authors.lastname: Keizer
authors.forename: Rolf
authors.initials: R
authors.lastname: van Hes
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: de Moes
authors.forename: Arnold P
authors.initials: AP
authors.lastname: den Hartog
authors.forename: Bob
authors.initials: B
authors.lastname: Stork
authors.forename: Rob H
authors.initials: RH
authors.lastname: Plekkenpol
authors.forename: Leonarda C
authors.initials: LC
authors.lastname: Niemann
authors.forename: Cees N J
authors.initials: CN
authors.lastname: Stroomer
authors.forename: Martin Th M
authors.initials: MT
authors.lastname: Tulp
authors.forename: Herman H
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.forename: Mayke B
authors.initials: MB
authors.lastname: Hesselink
authors.forename: Arnoud H J
authors.initials: AH
authors.lastname: Herremans
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D048588:Benzoxazines; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; C506289:8-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)-4H-benzo(1,4)oxazin-2-methyl-3-one