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.
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.
Feenstra
Roelof Willem
RW
Solvay Pharmaceuticals, Research Laboratories, C.J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands. rolf.feenstra@solvay.com
van den Hoogenband
Adri
A
Stroomer
Cornelis Nicolaas Jozef
CN
van Stuivenberg
Herman Heinrich
HH
Tulp
Martin Theodorus Maria
MT
Long
Stephen Kenneth
SK
van der Heyden
Johannes Antonius Maria
JA
Kruse
Cornelis Gerrit
CG
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
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