2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor

Bioorg Med Chem. 2000 Jun;8(6):1383-91. doi: 10.1016/s0968-0896(00)00062-6.

Abstract

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.

MeSH terms

  • Acetylcholine / metabolism
  • Amino Acid Sequence
  • Animals
  • Galanin / chemistry
  • Galanin / metabolism
  • Guinea Pigs
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Ileum / drug effects
  • Ileum / physiology
  • In Vitro Techniques
  • Male
  • Melanoma / pathology
  • Molecular Sequence Data
  • Rats
  • Receptors, Galanin
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Structure-Activity Relationship
  • Thiepins / chemistry
  • Thiepins / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Receptors, Galanin
  • Receptors, Neuropeptide
  • Thiepins
  • Galanin
  • Acetylcholine