The multiobjective based design, synthesis and evaluation of the arylsulfonamide/amide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT₇ receptor antagonists

Eur J Med Chem. 2012 Oct:56:348-60. doi: 10.1016/j.ejmech.2012.07.043. Epub 2012 Aug 4.

Abstract

An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24-95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT(7)R. Additionally, the targeted library members were tested for 5-HT(1A), 5-HT(6), and D(2) receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT(7)R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT(7)R ligand (K(i) = 0.3 nM) with strong antagonistic properties (K(b) = 1 nM) and a 1450-fold selectivity over 5-HT(1A)Rs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Cells, Cultured
  • Combinatorial Chemistry Techniques
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology*
  • Software
  • Structure-Activity Relationship

Substances

  • Amides
  • Ligands
  • Piperidines
  • Pyrrolidines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor