title: Small molecule antagonists of the bradykinin B1 receptor.
abstract: 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-Arglo-kallidin ([3H]-dAK) at IMR-90 cells expressing an endogenous human B1 receptor (Bmax = 20,000 receptors/cell, K(D) = 0.5+/-0.1 nM) or against membranes from 293E cells expressing a recombinant human B1 receptor (Bmax = 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 KI 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.
authors.affiliation: Pharmacopeia, CN5350, Princeton, NJ 08543-5350, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Horlick
authors.forename: M H
authors.initials: MH
authors.lastname: Ohlmeyer
authors.forename: I L
authors.initials: IL
authors.lastname: Stroke
authors.forename: B
authors.initials: B
authors.lastname: Strohl
authors.forename: G
authors.initials: G
authors.lastname: Pan
authors.forename: A E
authors.initials: AE
authors.lastname: Schilling
authors.forename: V
authors.initials: V
authors.lastname: Paradkar
authors.forename: J G
authors.initials: JG
authors.lastname: Quintero
authors.forename: M
authors.initials: M
authors.lastname: You
authors.forename: C
authors.initials: C
authors.lastname: Riviello
authors.forename: M B
authors.initials: MB
authors.lastname: Thorn
authors.forename: B
authors.initials: B
authors.lastname: Damaj
authors.forename: V D
authors.initials: VD
authors.lastname: Fitzpatrick
authors.forename: R E
authors.initials: RE
authors.lastname: Dolle
authors.forename: M L
authors.initials: ML
authors.lastname: Webb
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: N H
authors.initials: NH
authors.lastname: Sigal
mesh_terms: D001920:Bradykinin / Q000378:metabolism; D065168:Bradykinin Receptor Antagonists; D002460:Cell Line; D006801:Humans; D019151:Peptide Library; D043783:Receptor, Bradykinin B1; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D065168:Bradykinin Receptor Antagonists; D019151:Peptide Library; D043783:Receptor, Bradykinin B1; D001920:Bradykinin