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

Abstract

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 nM), and inhibited increases in intracellular calcium induced by desArg 10kallidin (desArg 10KD) (IC 50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K i 7.7nM), 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 10KD into the contralateral paw 24h 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 10KD-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. © 2005 Nature Publishing Group. All rights reserved.