Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2

J Med Chem. 2008 Nov 13;51(21):6980-7004. doi: 10.1021/jm8007097. Epub 2008 Oct 4.

Abstract

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.

MeSH terms

  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Cell Line
  • Cricetinae
  • Cross-Linking Reagents / chemistry
  • Humans
  • Molecular Structure
  • Rats
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin 5-HT1 Receptor Antagonists*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Structure-Activity Relationship

Substances

  • Antidepressive Agents
  • Benzopyrans
  • Cross-Linking Reagents
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Receptor, Serotonin, 5-HT1A