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

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. 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. 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. 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. 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. 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