Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor

1 We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP‐SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. 2 NVP‐SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (Ki 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (Ki 7.7 nM), NVP‐SAA164 showed no affinity for the rat B1 receptor expressed in Cos‐7 cells. 3 In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1‐KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1‐KO) mice following LPS treatment. 4 Freund's complete adjuvant‐induced mechanical hyperalgesia was similar in wild‐type and hB1‐KI mice, but was significantly reduced in mB1‐KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild‐type and hB1‐KI mice, but was absent in mB1‐KO animals. 5 Oral administration of NVP‐SAA164 produced a dose‐related reversal of FCA‐induced mechanical hyperalgesia and desArg10KD‐induced hyperalgesia in hB1‐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 B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man. British Journal of Pharmacology (2005) 144, 889–899. doi:10.1038/sj.bjp.0706139