Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles:: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor

被引：35
作者：
Sternfeld, F
Guiblin, AR
Jelley, RA
Matassa, VG
Reeve, AJ
Hunt, PA
Beer, MS
Heald, A
Stanton, JA
Sohal, B
Watt, AP
Street, LJ
机构：
[1] Merck Sharp & Dohme Ltd, Res Labs, Ctr Res Neurosci, Dept Chem, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Ltd, Res Labs, Ctr Res Neurosci, Dept Biochem, Harlow CM20 2QR, Essex, England
[3] Merck Sharp & Dohme Ltd, Res Labs, Ctr Res Neurosci, Dept Analyt, Harlow CM20 2QR, Essex, England
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 04期
关键词：
D O I：
10.1021/jm9805687
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1D alpha) receptors over h5-HT1B (formerly 5-HT1D beta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors, The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having g-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [S-35]GTP gamma S binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.
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收藏
页码：677 / 690
页数：14
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