N-methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist

It has been observed that reported 5-HT1D receptor agonists have at least o ne heteroatom (N, O, or S) on the 5-substituent of the indole. This has Zed to the hypothesis that a 5-substituent capable of participating in hydroge n bonding is critical far conveying high affinity. This article describes t he synthesis and biological evaluation of a new series of 5-alkyltryptamine analogues, which does not have a heteroatom in the 5-substituent group. In contrast to the hypothesis, 5-alkyltryptamines all exhibit high binding af finities for the human 5-HT1D receptor. The size of the lipophilic alkyl gr oup at the 5-position of the indole has significant impact on the 5-HT1D bi nding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affin ity (K-i < 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML -251.