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 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.
Scott
M K
MK
Drug Discovery Division, The R. W. Johnson Pharmaceutical Institute, Spring House, PA 19447, USA. scottm@prius.jnj.com
Ross
T M
TM
Lee
D H
DH
Wang
H Y
HY
Shank
R P
RP
Wild
K D
KD
Davis
C B
CB
Crooke
J J
JJ
Potocki
A C
AC
Reitz
A B
AB
D000109:Acetylcholine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019004:Galanin / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000473:pathology; D008969:Molecular Sequence Data; D051381:Rats; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013846:Thiepins / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide; D013846:Thiepins; D019004:Galanin; D000109:Acetylcholine