Studies toward the discovery of the next generation of antidepressants. Part 6: Dual 5-HT1A receptor and serotonin transporter affinity within a class of arylpiperazinyl-cyclohexyl indole derivatives.
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. zhoud@wyeth.com
Dahui
D
Zhou
Ping
P
Zhou
Deborah A
DA
Evrard
Kristin
K
Meagher
Michael
M
Webb
Boyd L
BL
Harrison
Donna M
DM
Huryn
Jeannette
J
Golembieski
Geoffrey A
GA
Hornby
Lee E
LE
Schechter
Deborah L
DL
Smith
Terrance H
TH
Andree
Richard E
RE
Mewshaw
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry*; D003514:Cyclohexylamines; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D003514:Cyclohexylamines; D007211:Indoles; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A