Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2.
Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.
Hatzenbuhler
Nicole T
NT
Chemical and Screening Sciences and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. hatzenn@wyeth.com
Baudy
Reinhardt
R
Evrard
Deborah A
DA
Failli
Amedeo
A
Harrison
Boyd L
BL
Lenicek
Steven
S
Mewshaw
Richard E
RE
Saab
Annmarie
A
Shah
Uresh
U
Sze
Jean
J
Zhang
Minsheng
M
Zhou
Dahui
D
Chlenov
Michael
M
Kagan
Michael
M
Golembieski
Jeannette
J
Hornby
Geoffrey
G
Lai
Margaret
M
Smith
Deborah L
DL
Sullivan
Kelly M
KM
Schechter
Lee E
LE
Andree
Terrance H
TH
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D001578:Benzopyrans; D003432:Cross-Linking Reagents; D044282:Receptor, Serotonin, 5-HT1A; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors