The influence of modifications in imide fragment structure on 5-HT(1A) and 5-HT(7) receptor affinity and in vivo pharmacological properties of some new 1-(m-trifluoromethylphenyl)piperazines

Bioorg Med Chem. 2007 Nov 15;15(22):7116-25. doi: 10.1016/j.bmc.2007.07.029. Epub 2007 Aug 22.

Abstract

New, flexible (7, 9, 11 and 13) and rigid (8, 10, 12 and 14) imides with a 1-(m-trifluorophenyl)piperazine fragment and a tetramethylene or a 1e,4e-cyclohexylene spacer, respectively, showed very high affinity (K(i)=0.3-34 nM) and agonistic in vivo activity for 5-HT(1A) receptors. Flexible new compounds and the previously described 5 also bound to 5-HT(7) receptors (K(i)=21-134 nM). Selected glutarimide derivatives, that is, the most potent postsynaptic 5-HT(1A) receptor agonist rigid compound 8 and its flexible analogue 7, as well as the previously described full agonist-rigid compound 6 and the partial agonist-its flexible counterpart 5 exhibited moderate affinity for alpha(1)-adrenoceptors (K(i)=85 - 268 nM), but were practically devoid of any affinity for dopamine D(2) sites. Those glutarimides demonstrated anxiolytic- (5 and 7) and antidepressant-like (5, 6 and 8) activity in the four-plate and the swim tests in mice, respectively; at the same time, however, they inhibited the locomotor activity of mice. The antidepressant-like effect of 8 was significantly stronger than that induced by imipramine used as a reference antidepressant.

MeSH terms

  • Animals
  • Body Temperature
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Imides / chemistry*
  • Ligands
  • Lip / drug effects
  • Maze Learning / drug effects
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Piperazines / administration & dosage
  • Piperazines / chemistry*
  • Piperazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptors, Serotonin / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swimming

Substances

  • Imides
  • Ligands
  • Piperazines
  • Receptors, Serotonin
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A
  • 1-(3-trifluoromethylphenyl)piperazine