Antihyperalgesic activity of a novel nonpeptide bradykinin B 1 receptor antagonist in transgenic mice expressing the human B 1 receptor

1 We describe the properties of a novel nonpeptide kinin B 1 receptor antagonist, NVP‐SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B 1 receptor. 2 NVP‐SAA164 showed high affinity for the human B 1 receptor expressed in HEK293 cells ( K i 8 n M ), and inhibited increases in intracellular calcium induced by desArg 10 kallidin (desArg 10 KD) (IC 50 33 n M ). While a similar high affinity was observed in monkey fibroblasts ( K i 7.7 n M ), NVP‐SAA164 showed no affinity for the rat B 1 receptor expressed in Cos‐7 cells. 3 In transgenic mice in which the native B 1 receptor was deleted and the gene encoding the human B 1 receptor was inserted (hB 1 knockin, hB 1 ‐KI), hB 1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B 1 receptor was detected in mouse B 1 receptor knockout (mB 1 ‐KO) mice following LPS treatment. 4 Freund's complete adjuvant‐induced mechanical hyperalgesia was similar in wild‐type and hB 1 ‐KI mice, but was significantly reduced in mB 1 ‐KO animals. Mechanical hyperalgesia induced by injection of the B 1 agonist desArg 10 KD into the contralateral paw 24 h following FCA injection was similar in wild‐type and hB 1 ‐KI mice, but was absent in mB 1 ‐KO animals. 5 Oral administration of NVP‐SAA164 produced a dose‐related reversal of FCA‐induced mechanical hyperalgesia and desArg 10 KD‐induced hyperalgesia in hB 1 ‐KI mice, but was inactive against inflammatory pain in wild‐type mice. 6 These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP‐SAA164 is a novel orally active B 1 receptor antagonist, providing further support for the utility of B 1 receptor antagonists in inflammatory pain conditions in man.British Journal of Pharmacology (2005) 144 , 889–899. doi: 10.1038/sj.bjp.0706139