Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia.
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
Burgess
G M
GM
Novartis Institute for Medical Sciences, 5 Gower Place, London, UK.
Perkins
M N
MN
Rang
H P
HP
Campbell
E A
EA
Brown
M C
MC
McIntyre
P
P
Urban
L
L
Dziadulewicz
E K
EK
Ritchie
T J
TJ
Hallett
A
A
Snell
C R
CR
Wrigglesworth
R
R
Lee
W
W
Davis
C
C
Phagoo
S B
SB
Davis
A J
AJ
Phillips
E
E
Drake
G S
GS
Hughes
G A
GA
Dunstan
A
A
Bloomfield
G C
GC
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy; D065168:Bradykinin Receptor Antagonists; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D066298:In Vitro Techniques; D007249:Inflammation / Q000150:complications*; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011759:Pyrrolidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D014599:Uterus / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D011759:Pyrrolidines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D013882:Thiosemicarbazones; C406475:bradyzide; D010738:Type C Phospholipases; D002118:Calcium