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 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.
Xu
Y C
YC
Discovery Chemistry Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Schaus
J M
JM
Walker
C
C
Krushinski
J
J
Adham
N
N
Zgombick
J M
JM
Liang
S X
SX
Kohlman
D T
DT
Audia
J E
JE
D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011869:Radioligand Assay; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*