title: Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor.
abstract: 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 hB(1)-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.
authors.affiliation: Novartis Institutes for Biomedical Research, 5 Gower Place, London WC1E 6BS. alyson.fox@pharma.novartis.com
authors.forename: Alyson
authors.initials: A
authors.lastname: Fox
authors.forename: Satbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Bifang
authors.initials: B
authors.lastname: Li
authors.forename: Moh
authors.initials: M
authors.lastname: Panesar
authors.forename: Uma
authors.initials: U
authors.lastname: Saha
authors.forename: Clare
authors.initials: C
authors.lastname: Davis
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dragoni
authors.forename: Sian
authors.initials: S
authors.lastname: Colley
authors.forename: Tim
authors.initials: T
authors.lastname: Ritchie
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.forename: Gillian
authors.initials: G
authors.lastname: Burgess
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D065169:Bradykinin B1 Receptor Antagonists; D019556:COS Cells; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D001549:Benzamides; D065169:Bradykinin B1 Receptor Antagonists; C504065:NVP-SAA164; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides