Novel Subtype-Selective Nonpeptide Bradykinin Receptor Antagonists FR167344 and FR173657

  1. Ichiro Aramori1,
  2. Junko Zenkoh1,
  3. Noriyuki Morikawa1,
  4. Nuala O’Donnell1,
  5. Masayuki Asano2,
  6. Kozo Nakamura1,
  7. Morita Iwami1,
  8. Hitoshi Kojo1 and
  9. Yoshitada Notsu1
  1. 1Molecular Biological Research Laboratory (I.A., J.Z., N.M., N.O., K.N., M.I., H.K., Y.N.) and 2Exploratory Research Laboratories (M.A.), Fujisawa Pharmaceutical Co., Ltd., Tsukuba 300–26, Japan

    Abstract

    We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline), for the human bradykinin receptor subtypes (B1 and B2). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the bradykinin receptor subtypes, FR167344 and FR173657 showed a high affinity binding to the B2 receptor with IC50 values of 65 and 8.9 nm, respectively, and no binding affinity for the B1 receptor. FR167344 and FR173657 inhibited the B2 receptor-mediated phosphatidylinositol (PI) hydrolysis and produced a concentration-dependent rightward shift in the dose-response curve to bradykinin. This shift was accompanied by a progressive reduction of maximal response. Estimated pA2 values for the antagonism of bradykinin-induced PI hydrolysis by FR167344 and FR173657 were 8.0 and 9.0, respectively. FR167344 and FR173657 showed no stimulatory effects on PI hydrolysis. Therefore, FR167344 and FR173657 are potent, highly selective, and insurmountable antagonists for the human bradykinin B2 receptor.

    Footnotes

    • Send reprint requests to: Ichiro Aramori, Ph.D., Molecular Biological Research Lab, Fujisawa Pharmaceutical Co., Ltd., 5–2-3 Tokodai, Tsukuba 300–26, Japan. E-mail:ichiro_aramori{at}rnd.fujisawa.co.jp

    • ↵1 N. Inamura, M. Asano, C. Hatori, H. Sawai, T. Fujiwara, A. Katayama, H. Kayakiri, S. Satoh, Y. Abe, T. Inoue, Y. Sawada, K. Nakahara, T. Oku, and M. Okuhara, unpublished observations.

    • ↵2 J. Zenkoh, I. Aramori, N. Morikawa, and Y. Notsu, unpublished observations.

    • Abbreviations:
      FR167344
      3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride
      FR173657
      8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline
      Hoe140
      d-Arg-[hydroxyproline3,β-thienylalanine4,d-Tic7,Oic8]bradykinin
      PCR
      polymerase chain reaction
      PI
      phosphatidylinositol
      IP1
      inositol monophosphate
      IP2
      inositol bisphosphate
      IP3
      inositol trisphosphate
      CHO
      Chinese hamster ovary
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      BSA
      bovine serum albumin
      PBS
      phosphate-buffered saline
      DR
      dose-ratio
      • Received October 2, 1996.
      • Accepted October 22, 1996.
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    1. Molecular Pharmacology February 1, 1997 vol. 51 no. 2 171-176
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