Small molecule antagonists of the bradykinin B1 receptor

被引：25

作者：

Horlick, RA ^{[1
]}

Ohlmeyer, MH ^{[1
]}

Stroke, IL ^{[1
]}

Strohl, B ^{[1
]}

Pan, GH ^{[1
]}

Schilling, AE ^{[1
]}

Paradkar, V ^{[1
]}

Quintero, JG ^{[1
]}

You, M ^{[1
]}

Riviello, C ^{[1
]}

Thorn, MB ^{[1
]}

Damaj, B ^{[1
]}

Fitzpatrick, VD ^{[1
]}

Dolle, RE ^{[1
]}

Webb, ML ^{[1
]}

Baldwin, JJ ^{[1
]}

Sigal, NH ^{[1
]}

机构：

[1] Pharmacopeia, Princeton, NJ 08543 USA

来源：

IMMUNOPHARMACOLOGY | 1999年 / 43卷 / 2-3期

关键词：

combinatorial chemistry; chemical libraries; receptor binding; receptor signaling; high-throughput screening; GPCR;

D O I：

10.1016/S0162-3109(99)00130-7

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Screening Pharmacopeia's encoded combinatorial libraries has led to the identification of potent, selective, competitive antagonists at the bradykinin B1 receptor. Libraries were screened using a displacement assay of [H-3]-des-Arg (10)-kallidin ([H-3]-dAK) at IMR-90 cells expressing an endogenous human B1 receptor (B-max = 20,000 receptors/cell, K-D = 0.5 +/- 0.1 nM) or against membranes from 293E cells expressing a recombinant human B1 receptor (B-max = 8,000 receptors/cell, K-D = 0.5 +/- 0.3 nM). Compound PS020990, an optimized, representative member from the class of compounds, inhibits specific binding of H-3-dAK at IMR-90 cells with a K-1 of 6 +/- 1 nM. The compound inhibits dAK-induced phosphatidyl inositol turnover( K-Bapp = 0.4 +/- 0.2 nM) and calcium mobilization (K-Bapp = 17 +/- 2 nM) in IMR-90 cells. Compounds from the lead series are inactive at the B2 receptor and are > 1000-fold specific for BI vs. a variety of other receptors, ion channels and enzymes. PS020990 and other related chemotypes therefore offer an excellent opportunity to explore further the role of B1 receptors in disease models and represent a potential therapeutic avenue. (C) 1999 Elsevier Science B.V. All rights reserved.

引用

页码：169 / 177

页数：9

共 21 条

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