1-(2-Aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-e]indole: a rotationally restricted phenolic analog of the neurotransmitter serotonin and agonist selective for serotonin (5-HT2-type) receptors

J Med Chem. 1992 Oct 2;35(20):3625-32. doi: 10.1021/jm00098a005.


A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]-indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT1 receptors but equal or greater affinity for 5-HT2 receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT2 receptor antagonists establishing these tryptamines as selective 5-HT2 receptor agonists. The high affinity and potency of 5 for 5-HT2 receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT2 receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT2 receptors coupled with their poor affinity for 5-HT1 receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT1 versus 5-HT2 receptors.

MeSH terms

  • Animals
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology
  • Rats
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism
  • Serotonin / analogs & derivatives*
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship


  • Indoles
  • Pyridines
  • Pyrroles
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one
  • CP 132484
  • Serotonin