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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页码：677 / 690

页数：14

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