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 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 nM), and inhibited increases in intracellular calcium induced by desArg(10)kallidin (desArg(10)KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K-i 7.7 nM), 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 B1 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.