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

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the gal anin 1 receptor(GAL-R1). Using an HTS assay based on I-125-human galanin bi nding to the human galanin-l receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affini ty IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin anal ogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in second ary assays involving adenylate cyclase activity and GTP binding to G-protei ns. Analogues 7 and 23 were also active in functional assays involving gala nin, reversing the inhibitory effect of galanin on acetylcholine (ACh) rele ase in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch. (C) 2000 Elsevier Science Ltd. All rights reserved.