Synthesis and serotonergic activity of 5-(oxadiazolyl)tryptamines: potent agonists for 5-HT1D receptors

J Med Chem. 1993 May 28;36(11):1529-38. doi: 10.1021/jm00063a003.


The synthesis and 5-HT1D receptor activity of a novel series of 5-(oxadiazolyl)tryptamines is described. Modifications of the oxadiazole 3-substituent, length of the linking chain (n), and the amine substituents are explored and reveal a large binding pocket in the 5-HT1D receptor domain. Oxadiazole substituents such as benzyl are accommodated without loss of agonist potency or efficacy. The incorporation of polar functionality on a phenyl or benzyl spacer group results in a 10-fold increase in affinity and functional potency. Optimal 5-HT1D activity is observed when the heterocycle is conjugated with the indole and the benzyl sulfonamides 20t and 20u represent some of the most potent 5-HT1D agonists known. Replacement of O for S in the heterocycle leads to a further increase in potency. Deletion of oxadiazole N-2 does not reduce activity, suggesting the requirement for only one H-bond acceptor in this location. The selectivity of these compounds for 5-HT1D receptors over other serotonergic receptors is discussed. Sulfonamide 20t shows > or = 1000-fold selectivity for 5-HT1D over 5-HT2, 5-HT1C, and 5-HT3 receptors and 10-fold selectivity with respect to 5-HT1A receptors. The functional activity of this series of compounds is studied and demonstrates high 5-HT1D receptor potency and efficacy comparable to that of 5-HT.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • In Vitro Techniques
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / metabolism
  • Oxadiazoles / pharmacology
  • Rabbits
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship
  • Swine
  • Tryptamines / chemical synthesis*
  • Tryptamines / metabolism
  • Tryptamines / pharmacology
  • Vasoconstriction / drug effects


  • Oxadiazoles
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Tryptamines