Bradyzide, a potent non‐peptide B2 bradykinin receptor antagonist with long‐lasting oral activity in animal models of inflammatory hyperalgesia

• Published in: British journal of pharmacology Vol. 129; no. 1; pp. 77 - 86
• Main Authors: Burgess, Gillian M, Perkins, Martin N, Rang, Humphrey P, Campbell, Elizabeth A, Brown, Michael C, McIntyre, Peter, Urban, Laszlo, Dziadulewicz, Edward K, Ritchie, Timothy J, Hallett, Allan, Snell, Christopher R, Wrigglesworth, Roger, Lee, Wai, Davis, Clare, Phagoo, Steve B, Davis, Andrew J, Phillips, Elsa, Drake, Gillian S, Hughes, Glyn A, Dunstan, Andrew, Bloomfield, Graham C
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2000; Nature Publishing
• Subjects: [3H]‐bradykinin binding; B2 bradykinin receptor; Biological and medical sciences; hyperalgesia; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; non‐peptide bradykinin antagonist; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Spinal cord; Rat; Rodentia; Central nervous system; Oral administration; Molecular interaction; Inflammation; In vitro; Hyperalgesia; In vivo; Vertebrata; Biological fixation; Mammalia; Transfection; Uterus; Animal; Bradykinin; Female genital system; Peptidergic receptor; Blood pressure; Antagonist; Hemodynamics; Calcium Cations
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703012

Bradyzide is from a novel class of rodent‐selective non‐peptide B2 bradykinin antagonists (1‐(2‐Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B2 receptor, displacing [3H]‐bradykinin binding in NG108‐15 cells and in Cos‐7 cells expressing the rat receptor with KI values of 0.51±0.18 nM (n=3) and 0.89±0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B2 receptor‐induced 45Ca efflux from NG108‐15 cells with a pKB 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 (IC50 value; 1.6±0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B2 receptor, displacing [3H]‐bradykinin binding in human fibroblasts and in Cos‐7 cells expressing the human B2 receptor with KI values of 393±90 nM (n=3) and 772±144 nM (n=3), respectively. Bradyzide inhibits bradykinin‐induced [3H]‐inositol trisphosphate (IP3) formation with IC50 values of 11.6±1.4 nM (n=3) at the rat and 2.4±0.3 μM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B1 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 (ED50, 0.84 μmol 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 B2 bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77–86; doi:10.1038/sj.bjp.0703012