Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia

Br J Pharmacol. 2000 Jan;129(1):77-86. doi: 10.1038/sj.bjp.0703012.


Bradyzide is from a novel class of rodent-selective non-peptide B(2) bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with K(I) values of 0.51+/-0.18 nM (n=3) and 0.89+/-0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B(2) receptor-induced (45)Ca efflux from NG108-15 cells with a pK(B) of 8.0+/-0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC(50) value; 1.6+/-0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B(2) receptor with K(I) values of 393+/-90 nM (n=3) and 772+/-144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [(3)H]-inositol trisphosphate (IP(3)) formation with IC(50) values of 11.6+/-1.4 nM (n=3) at the rat and 2.4+/-0.3 microM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B(1) bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED(50), 0.84 micromol kg(-1); duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B(2) bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77 - 86

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Experimental / complications
  • Arthritis, Experimental / drug therapy
  • Bradykinin Receptor Antagonists*
  • COS Cells
  • Calcium / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • In Vitro Techniques
  • Inflammation / complications*
  • Membranes / drug effects
  • Membranes / metabolism
  • Pregnancy
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology*
  • Rats
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / biosynthesis
  • Receptors, Bradykinin / drug effects
  • Receptors, Bradykinin / metabolism
  • Thiosemicarbazones / administration & dosage
  • Thiosemicarbazones / metabolism
  • Thiosemicarbazones / pharmacology*
  • Tumor Cells, Cultured
  • Type C Phospholipases / metabolism
  • Uterus / drug effects


  • Anti-Inflammatory Agents, Non-Steroidal
  • Bradykinin Receptor Antagonists
  • Pyrrolidines
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • Thiosemicarbazones
  • bradyzide
  • Type C Phospholipases
  • Calcium