Introduction of a methyl group in alpha- or beta-position of 1-heteroarylethyl-4-phenylpiperazines affects their dopaminergic/serotonergic properties

Arch Pharm (Weinheim). 2001 Dec;334(12):375-80. doi: 10.1002/1521-4184(200112)334:12<375::AID-ARDP375>3.0.CO;2-P.

Abstract

1-(2-Heteroarylalkyl)-4-phenylpiperazines containing methyl group in either the alpha- or the beta-position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D1 receptor-selective), spiperone (D2 receptor-selective), and 8-OH-DPAT (5-HT1A receptor-selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D2 receptor (10b-13b), and decreased the affinity for the 5-HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8-OH-DPAT. Most potent of the newly synthesized compounds in [3H]spiperone assay were compounds (+/-)6-[1-methyl-2- (4-phenylpiperazin-1-yl)-ethyl]-1,4-dihydroquinoxaline-2,3-dione (10b), Kd = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoimidazol- 2-thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D2 receptor, while the affinity for the 5-HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds (14-17) run in the same binding assays as references.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Dopamine Agents / chemical synthesis*
  • Dopamine Agents / chemistry
  • Dopamine Agents / metabolism
  • Humans
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Radioligand Assay
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin Agents / chemical synthesis*
  • Serotonin Agents / chemistry
  • Serotonin Agents / metabolism
  • Structure-Activity Relationship

Substances

  • Dopamine Agents
  • Piperazines
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin Agents