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

Abstract

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) (IC 50 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 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. 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.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…In the above-mentioned models of neuropathic pain based on direct lesion of the sciatic nerve and inducing some kind of inflammation and sprouting, heat hyperalgesia was consistently shown to be mediated by both B 2 and B 1 receptors (183, 241,428,444,573,784). Regarding mechanical allodynia, a role for B 1 receptors was revealed in some (183, 784) but not other studies (205,573).…”

“…B 1 receptor induction by bacterial lipopolysaccharide (LPS) was inhibited by glucocorticoid pretreatment, cyclooxygenase (COX) blockade, and agents inhibiting the synthesis or action of TNF-␣ (82,84,205,608); moreover, endogenous glucocorticoid hormones were shown to exert a tonic inhibitory control on receptor expression through a NF-B-mediated pathway (78). In a model of experimental colitis in mice, B 1 receptor upregulation depended on de novo protein synthesis, NF-B activation, TNF-␣ production, and inducible NO synthase (iNOS) activity (267).…”

Pharmacological, Pharmacokinetic, and Primate Analgesic Efficacy Profile of the Novel Bradykinin B1 Receptor Antagonist ELN441958

“…For example, Su et al (2003) exploited the pharmacological similarity between primate and rabbit B 1 receptors by demonstrating the potent efficacy of a quinoxaline B 1 receptor antagonist in a CFA-induced hyperalgesia in rabbits. In an elegant study by Fox et al (2005), the highly human-selective B 1 receptor antagonist NVP-SAA164 reversed CFA-induced hyperalgesia in transgenic mice expressing only the human B 1 receptor. An alternative approach is to evaluate compounds in primate pain models.…”

4 Animal models in the kinin fi eld

“…Among the many different animal models generated in this fi eld, there are knockout mice for the kinin B 1 (B 1 R ) and B 2 (B 2 R ) receptors (B1KO and B2KO , respectively) and also for both receptors together (B1B2KO , BRKO ). These kinin knockout mice have been crossed with other models like: the ob/ob mice (ob/ob-B 1 Ϫ/Ϫ ) (Mori et al, 2008b); apoE Ϫ/Ϫ mice (apoE Ϫ/Ϫ /B 1 Ϫ/Ϫ (Ni et al, 2003); the rat with overexpression of human B 1 R (Hess et al, 2004); and the mouse expressing the human B 1 R, hB 1 -KI (Fox et al, 2005).…”

“…The conservation in amino acid identity from rodent to human is only 73% (Leeb-Lundberg et al, 2005), and the affi nity of the human B 1 R for des-Arg 10 kallidin (DAKD)-derived peptides is signifi cantly higher than that found for rodent receptors. In order to create a model to mimic the specifi city of drug effect in humans, Hess et al (2004) and Fox et al (2005) reported the generation of a transgenic animal expressing the human B 1 R by two different approaches.…”