Synthesis and Serotonergic Activity of 5-(Oxadiazolyl)tryptamines: Potent Agonists for 5-HT1D Receptors

Article abstract of DOI:10.1021/jm00063a003

The synthesis and 5-HT_1D 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-HT_1D 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-HT_1D 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-HT_1D agonist 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 requirements for only one H-bond acceptor in this location.The selectivity of these compounds for 5-HT_1D receptors over other serotonergic receptors is discussed.Sulfonamide 20t shows <*> 1000-fold selectivity for 5-HT_1D over 5-HT₂, 5-HT_1C, and 5-HT₃ receptors and 10-fold selectivity with respect to 5-HT_1A receptors.The functional activity of this series of compounds is studied and demonstrates high 5-HT_1D receptor potency and efficacy comparable to that of 5-HT.