N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist.
Article Details
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Xu YC, Schaus JM, Walker C, Krushinski J, Adham N, Zgombick JM, Liang SX, Kohlman DT, Audia JE
N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist.
J Med Chem. 1999 Feb 11;42(3):526-31.
- PubMed ID
- 9986723 [ View in PubMed]
- Abstract
It has been observed that reported 5-HT1D receptor agonists have at least one heteroatom (N, O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent capable of participating in hydrogen bonding is critical for conveying high affinity. This article describes the 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 affinities for the human 5-HT1D receptor. The size of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT1D binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affinity (Ki < 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML-251.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Frovatriptan 5-hydroxytryptamine receptor 1B Ki (nM) 10.3 N/A N/A Details Frovatriptan 5-hydroxytryptamine receptor 1D Ki (nM) 4.4 N/A N/A Details Naratriptan 5-hydroxytryptamine receptor 1A Ki (nM) 45 N/A N/A Details Naratriptan 5-hydroxytryptamine receptor 1B Ki (nM) 3.3 N/A N/A Details Naratriptan 5-hydroxytryptamine receptor 1D Ki (nM) 2.3 N/A N/A Details Naratriptan 5-hydroxytryptamine receptor 1D EC 50 (nM) 1.6 N/A N/A Details Rizatriptan 5-hydroxytryptamine receptor 1B Ki (nM) 10.1 N/A N/A Details Rizatriptan 5-hydroxytryptamine receptor 1D Ki (nM) 4.3 N/A N/A Details Rizatriptan 5-hydroxytryptamine receptor 1D EC 50 (nM) 3 N/A N/A Details Sumatriptan 5-hydroxytryptamine receptor 1A Ki (nM) 230 N/A N/A Details Sumatriptan 5-hydroxytryptamine receptor 1B Ki (nM) 9.6 N/A N/A Details Sumatriptan 5-hydroxytryptamine receptor 1D EC 50 (nM) 4.3 N/A N/A Details Sumatriptan 5-hydroxytryptamine receptor 1D Ki (nM) 4.4 N/A N/A Details