SB-705498

501951-42-4

C17H16BrF3N4O

H2O : < 0.1 mg/mL (insoluble); DMSO : >= 100 mg/mL (232.98 mM)

Membrane Transporter/Ion Channel; Neuronal Signaling

SB-705498 is a potent, selective and orally bioavailable transient receptor potential vanilloid 1 (TRPV1) receptor antagonist with a pIC₅₀ of 7.1. IC50 & Target: pIC50: 7.1 In Vitro: SB705498 (0.3 nM-1 uM) potently inhibits capsaicin-induced activation of human TRPV1 expressed in 1321N1 cells or HEK293 cells with apparent pK_i of 7.5 or 7.6, respectively. Coapplication of 100 nM SB705498 rapidly, completely and reversibly inhibits hTRPV1 expressed in HEK293 cells. SB705498 has no significant effect on endogenous [Ca²⁺] responses in HEK293 cells produced by muscarinic acetylcholine receptor activation with carbachol or store-operated channel-mediated Ca²⁺ entry after depletion of intracellular stores with the Ca²⁺ pump inhibitor thapsigargin. SB705498 (10 pM-1 uM) also has no significant antagonist effect versus the close TRPV1 receptor paralog TRPV4 transiently expressed in HEK293 cells and activated using the synthetic ligand 4alpha-phorbol-12, 13-didecanoate (10 uM). SB705498 reveals good antagonist potency against both the rat and guinea pig TRPV1. SB705498 antagonizes rat and guinea pig TRPV1 with pK_i of 7.5 and 7.3, respectively. Coapplication of 100 nM to 10 uM SB705498 to the steady state of a maintained capsaicin response leads to rapid and complete inhibition of hTRPV1 at -70 mV. SB705498 inhibits capsaicin-mediated activation of hTRPV1 with IC₅₀ of 3 nM and 17 nM at positive and negative holding potentials (-70 mV and + 70 mV), respectively. Coapplication of 1 uM SB705498 to the plateau period of the response produces complete and reversible inhibition of the TRPV1-mediated conductance^[1]. SB705498 shows approximately equal activity versus multiple and diverse chemical and physical modes of TRPV1 receptor activation. SB705498 shows little or no activity versus a wide range of ion channels, receptors and enzymes. SB705498 produces full blockade of heat as well as pH activation of hTRPV1^[2]. In Vivo: SB705498 exhibits potent and reversible blockade against the multiple modes of TRPV1 activation, namely the vanilloid (capsaicin), heat- and acid-mediated activation of the receptor. SB705498 displays excellent activity at 10 and 30 mg/kg po with good reversal of allodynia. SB705498 (10 mg/kg p.o.) gives 80% reversal of allodynia in the guinea pig FCA model^[2].