Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4409-13. doi: 10.1016/j.bmcl.2003.09.025.


A novel series of highly potent human 5-HT(1D) agonists, dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine, was synthesized. Structure-activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K(i)=2.4 nM) agonist at the human 5-HT(1D) receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F(po)=51%).

MeSH terms

  • Administration, Oral
  • Amines / chemical synthesis*
  • Amines / pharmacology*
  • Binding Sites
  • Biological Availability
  • Drug Design
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology*
  • Kinetics
  • Molecular Conformation
  • Receptor, Serotonin, 5-HT1B / chemistry
  • Receptor, Serotonin, 5-HT1B / drug effects*
  • Receptor, Serotonin, 5-HT1B / physiology
  • Serotonin Receptor Agonists / administration & dosage
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship


  • Amines
  • Indoles
  • Receptor, Serotonin, 5-HT1B
  • Serotonin Receptor Agonists