| Autor: |
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 |
| Zdroj: |
British Journal of Pharmacology; January 2000, Vol. 129 Issue: 1 p77-86, 10p |
| Abstrakt: |
Bradyzide is from a novel class of rodent‐selective non‐peptide B2bradykinin antagonists (1‐(2‐Nitrophenyl)thiosemicarbazides).Bradyzide has high affinity for the rodent B2receptor, displacing [3H]‐bradykinin binding in NG108‐15 cells and in Cos‐7 cells expressing the rat receptor with KIvalues of 0.51±0.18 nM(n=3) and 0.89±0.27 nM(n=3), respectively.Bradyzide is a competitive antagonist, inhibiting B2receptor‐induced 45Ca efflux from NG108‐15 cells with a pKBof 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 (IC50value; 1.6±0.05 nM(n=3)).Bradyzide is much less potent at the human than at the rodent B2receptor, displacing [3H]‐bradykinin binding in human fibroblasts and in Cos‐7 cells expressing the human B2receptor with KIvalues of 393±90 nM(n=3) and 772±144 nM(n=3), respectively. Bradyzide inhibits bradykinin‐induced [3H]‐inositol trisphosphate (IP3) formation with IC50values 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 B1bradykinin 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 B2bradykinin receptor, with selectivity for the rodent over the human receptor. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Plný text