SB705498 is a TRPV1 antagonist for hTRPV1. SB-705498 has been investigated for the treatment of Rhinitis, Chronic Cough, and Non-allergic Rhinitis.

TRPV1 (human):7.1(pIC50), TRPV1 (human):7.6(pKi)

SB705498 (0.3 nM-1 μM) effectively blocks capsaicin-induced activation of human TRPV1 channels in 1321N1 and HEK293 cells, with apparent pKi values of 7.5 and 7.6, respectively. A 100 nM SB705498 coapplication rapidly, completely, and reversibly suppresses hTRPV1 in HEK293 cells, without significantly affecting [Ca2+] responses induced by carbachol activation of muscarinic acetylcholine receptors or Ca2+ entry through store-operated channels following thapsigargin-induced Ca2+ store depletion. SB705498 also shows negligible antagonistic effects on TRPV4 activation in HEK293 cells within the 10 pM to 1 μM range and selectively inhibits TRPV1, demonstrating notable potency against rat and guinea pig TRPV1 with pKi values of 7.5 and 7.3, respectively. At 100 nM-10 μM, it rapidly and completely inhibits hTRPV1 in sustained capsaicin responses at -70 mV, with IC50 values of 3 nM and 17 nM at -70 mV and +70 mV, respectively. Furthermore, 1 μM SB705498 fully and reversibly inhibits TRPV1-mediated conductance during the response plateau, uniformly blocking both chemical and physical TRPV1 activation with minimal to no activity against other ion channels, receptors, and enzymes, including inhibition of TRPV1 by heat and altered pH levels.

SB705498 demonstrates potent and reversible inhibition of TRPV1 receptor activation through various modes, including vanilloid (capsaicin), heat, and acid mediation. It shows remarkable efficacy at 10 and 30 mg/kg orally, effectively reversing allodynia. Additionally, SB705498 achieves an 80% reduction in allodynia within the guinea pig FCA model at a dosage of 10 mg/kg orally [2].