Abstract

The therapeutic potential of TRPV1 antagonists for chronic pain has been recognised for over a decade. However, pre-clinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation resulting in hyperthermia, which is a major hurdle for clinical development of these drugs. Here we describe the properties of BCTP, a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classical polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC50 values of 65.4 nM and 26.4 nM, respectively. Similar activity was observed at rat TRPV1 and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D50 value of 2 mg/kg, p.o.. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through inhibition of TRPV1. Surprisingly, BCTP administered orally induced only a maximal 0.6 °C increase in core body temperature at the highest tested doses (30 and 100mg/kg), contrasting markedly with AMG517, a clinically tested TRPV1 antagonist, which induced marked hyperthermia (>1 °C) at doses eliciting sub-maximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classical polymodal inhibition profile can be identified where the analgesic action is separated from effects on body temperature.