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

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.NVP-SAA164 showed high affinity for the human B₁ receptor expressed in HEK293 cells (K_i 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 (K_i 7.7?nM), NVP-SAA164 showed no affinity for the rat B₁ receptor expressed in Cos-7 cells.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.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.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.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 [ABSTRACT FROM AUTHOR]