Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs.
Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.
Kling
Andreas
A
Neuroscience Discovery, Abbott GmbH & Co. KG, D-67008 Ludwigshafen, Germany. andreas.kling@abbott.com
Lange
Udo E W
UE
Mack
Helmut
H
Bakker
Margot H M
MH
Drescher
Karla U
KU
Hornberger
Wilfried
W
Hutchins
Charles W
CW
Möller
Achim
A
Müller
Reinhold
R
Schmidt
Martin
M
Unger
Liliane
L
Wicke
Karsten
K
Schellhaas
Kurt
K
Steiner
Gerd
G
D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
C433863:5-chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1-(4-(pyridin-4-yl)naphth-1-ylaminocarbonyl)-1H-indole; D000928:Antidepressive Agents; D007211:Indoles; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists