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

被引：84

作者：

Burgess, GM ^{[1
]}

Perkins, MN ^{[1
]}

Rang, HP ^{[1
]}

Campbell, EA ^{[1
]}

Brown, MC ^{[1
]}

McIntyre, P ^{[1
]}

Urban, L ^{[1
]}

Dziadulewicz, EK ^{[1
]}

Ritchie, TJ ^{[1
]}

Hallett, A ^{[1
]}

Snell, CR ^{[1
]}

Wrigglesworth, R ^{[1
]}

Lee, W ^{[1
]}

Davis, C ^{[1
]}

Phagoo, SB ^{[1
]}

Davis, AJ ^{[1
]}

Phillips, E ^{[1
]}

Drake, GS ^{[1
]}

Hughes, GA ^{[1
]}

Dunstan, A ^{[1
]}

Bloomfield, GC ^{[1
]}

机构：

[1] Novartis Inst Med Sci, London WC1E 6BN, England

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2000年 / 129卷 / 01期

关键词：

B-2 bradykinin receptor; non-peptide bradykinin antagonist; H-3]-bradykinin binding; hyperalgesia;

D O I：

10.1038/sj.bjp.0703012

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

1 Bradyzide is from a novel class of rodent-selective non-peptide B-2 bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). 2 Bradyzide has high affinity for the rodent B-2 receptor, displacing [H-3]-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. 3 Bradyzide is a competitive antagonist, inhibiting B-2 receptor-induced Ca-45 efflux from NG108-15 cells with a pK(B) of 8.0 +/- 0.16 (n = 5) and a Schild slope of 1.05. 4 In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC50 value; 1.6 +/- 0.05 nM (n = 3)). 5 Bradyzide is much less potent at the human than at the rodent B-2 receptor, displacing [H-3]-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 [H-3]-inositol trisphosphate (IP3) formation with IC50 values of 11.6 +/- 1.4 nM (n = 3) at the rat and 2.4 +/- 0.3 mu M (n = 3) at the human receptor. 6 Bradyzide does not interact with a range of other receptors, including human and rat B-1 bradykinin receptors. 7 Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. 8 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 mu mol 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; 9 In summary, bradyzide is a potent, orally active, antagonist of the B-2 bradykinin receptor, with selectivity for the rodent over the human receptor.

引用

页码：77 / 86

页数：10

共 38 条

[1] A novel class of orally active non-peptide bradykinin B2 receptor antagonists.: 4.: Discovery of novel frameworks mimicking the active conformation [J].