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Bradyzide, a potent non-peptide B2bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia

journal contribution
posted on 2023-06-08, 20:57 authored by Gillian M Burgess, Martin N Perkins, Humphrey P Rang, Elizabeth A Campbell, Michael C Brown, Peter McIntyre, Laszlo Urban, Edward K Dziadulewicz, Timothy J Ritchie, Allan Hallett, Christopher R Snell, Roger Wrigglesworth, Wai Lee, Clare Davis, Steve B Phagoo, Andrew J Davis, Elsa Phillips, Gillian S Drake, Glyn A Hughes, Andrew Dunstan, Graham C Bloomfield
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.


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British Journal of Pharmacology




Nature Publishing Group





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  • Chemistry Publications

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