SB705498 TRP Channel antagonist

SB705498 (0.3 nM-1 μM) 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 this compound rapidly, completely and reversibly inhibits hTRPV1 expressed in HEK293 cells. This chemical 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. This compound (10 pM-1 μM) also has no significant antagonist effect versus the close TRPV1 receptor paralog TRPV4 transiently expressed in HEK293 cells and activated using the synthetic ligand 4α-phorbol-12,13-didecanoate (10 μM). This chemical reveals good antagonist potency against both the rat and guinea pig TRPV1. It antagonises rat and guinea pig TRPV1 with pK_i of 7.5 and 7.3, respectively. Coapplication of 100 nM to 10 μM this compound to the steady state of a maintained capsaicin response leads to rapid and complete inhibition of hTRPV1 at -70 mV. It 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 μM this chemical to the plateau period of the response produces complete and reversible inhibition of the TRPV1-mediated conductance. [1] This compound shows approximately equal activity versus multiple and diverse chemical and physical modes of TRPV1 receptor activation. It shows little or no activity versus a wide range of ion channels, receptors and enzymes. This chemical produces full blockade of heat as well as pH activation of hTRPV1. [2]

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. This compound displays excellent activity at 10 and 30 mg/kg po with good reversal of allodynia. It is also shown to give 80% reversal of allodynia in the guinea pig FCA model at 10 mg/kg p.o.. [2]