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Bradyzide, a potent non‐peptide B 2 bradykinin receptor antagonist with long‐lasting oral activity in animal models of inflammatory hyperalgesia
Author(s) -
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
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703012
Subject(s) - bradykinin , bradykinin receptor , receptor , receptor antagonist , chemistry , antagonist , extravasation , agonist , pharmacology , medicine , endocrinology , biology , biochemistry , immunology
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 n M ( n =3) and 0.89±0.27 n M ( 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 n M ( 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 n M ( n =3) and 772±144 n M ( n =3), respectively. Bradyzide inhibits bradykinin‐induced [ 3 H]‐inositol trisphosphate (IP 3 ) formation with IC 50 values of 11.6±1.4 n M ( n =3) at the rat and 2.4±0.3 μ M ( 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 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 B 2 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