Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands

J Med Chem. 2005 Mar 24;48(6):1781-95. doi: 10.1021/jm049615n.

Abstract

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.

MeSH terms

  • Adenylyl Cyclases / biosynthesis
  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry
  • Cell Line
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ligands
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Radioligand Assay
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Benzoxazines
  • Indoles
  • Ligands
  • N-(3-(2-diethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide
  • N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide
  • N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloronaphthalene-2-sulfonamide
  • Piperidines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Sulfonamides
  • serotonin 6 receptor
  • Adenylyl Cyclases