title: SAR study of 1-aryl-4-(phenylarylmethyl)piperazines as ligands for both dopamine D2 and serotonin 5-HT1A receptors showing varying degrees of (Ant)agonism. Selection of a potential atypical antipsychotic.
abstract: The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D(2) and serotonin 5-HT(1A) receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D(2) receptor antagonism and 5-HT(1A) receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.
authors.affiliation: Solvay Pharmaceuticals, Research Laboratories, C.J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands. rolf.feenstra@solvay.com
authors.forename: Roelof Willem
authors.initials: RW
authors.lastname: Feenstra
authors.forename: Adri
authors.initials: A
authors.lastname: van den Hoogenband
authors.forename: Cornelis Nicolaas Jozef
authors.initials: CN
authors.lastname: Stroomer
authors.forename: Herman Heinrich
authors.initials: HH
authors.lastname: van Stuivenberg
authors.forename: Martin Theodorus Maria
authors.initials: MT
authors.lastname: Tulp
authors.forename: Stephen Kenneth
authors.initials: SK
authors.lastname: Long
authors.forename: Johannes Antonius Maria
authors.initials: JA
authors.lastname: van der Heyden
authors.forename: Cornelis Gerrit
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D058829:Serotonin 5-HT1 Receptor Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C504317:1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-((5-(4-fluorophenyl)-3-pyridinyl)methyl)piperazine; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists