Synthesis and structure-activity relationships of a new model of arylpiperazines. Part 7: Study of the influence of lipophilic factors at the terminal amide fragment on 5-HT(1A) affinity/selectivity

Bioorg Med Chem. 2004 Mar 15;12(6):1551-7. doi: 10.1016/j.bmc.2003.12.006.

Abstract

The influence of lipophilic factors at the amide fragment of a new series of (+/-)-7a-alkyl-2-[4-(4-arylpiperazin-1-yl)butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 2 and of (+/-)-7a-alkyl-2-[(4-arylpiperazin-1-yl)methyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 3 has been studied. Variations of logP have been carried out by introducing different hydrocarbonated substituents (R(1)) at the position 7a of the bicyclohydantoin, namely the non-pharmacophoric part. All the new compounds exhibit high potency for the 5-HT(1A) receptor; however, affinities for the alpha(1) receptor are high for compounds 2a-l while compounds 3a-f are selective over this adrenergic receptor. On the other hand, differences in logP do not notably affect the K(i) values for the above receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Bridged-Ring Compounds / chemical synthesis*
  • Bridged-Ring Compounds / chemistry
  • Bridged-Ring Compounds / pharmacology
  • Hydantoins / chemistry*
  • Lipid Metabolism
  • Lipids / chemistry*
  • Male
  • Models, Molecular
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Serotonin, 5-HT1 / metabolism*
  • Structure-Activity Relationship

Substances

  • Amides
  • Bridged-Ring Compounds
  • Hydantoins
  • Lipids
  • Piperazines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Serotonin, 5-HT1