Small molecule antagonists of the bradykinin B1 receptor

Robert A. Horlick, Michael H. Ohlmeyer, Ilana L. Stroke, Barbara Strohl, Gonghua Pan, Adriane E. Schilling, Vidyadhar Paradkar, Jorge G. Quintero, Ming You, Christopher Riviello, Megan B. Thorn, Bassam Damaj, V. Danial Fitzpatrick, Roland E. Dolle, Maria L. Webb, John J. Baldwin, Nolan H. Sigal

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 [3H]-des-Arg10-kallidin ([3H]-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 3H-dAK at IMR-90 cells with a K(I) 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 B1 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. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)169-177
Number of pages9
Issue number2-3
StatePublished - Sep 1999


  • Chemical libraries
  • Combinatorial chemistry
  • GPCR
  • High-throughput screening
  • Receptor binding
  • Receptor signaling


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