Editors’ note: PRF member Michel Paré is president and co-founder of PhylogenX, a contract research organization in Montreal, Canada. Paré submitted the following comment about a new TRPV1 blocker entering clinical study. We invited PRF member Arpad Szallasi, who studies TRP channels at Monmouth Medical Center, Long Branch, New Jersey, US, to add his thoughts, which appear after Paré’s comment. We invite our readers to submit their own comments below.
The first generation of TRPV1 blockers tested for analgesic efficacy demonstrated undesirable side effects such as dysregulation of core body temperature (AMG517; AZD1386; ABT-102; MK-2295) or loss of sensitivity to heat pain (ABT-102, MK-2295). These side effects, which are also found in preclinical studies, are hypothesized to depend on the specific TRPV1 gating modalities (heat, pH, and capsaicin) targeted by the antagonists (Lehto et al., 2008; Reilly et al., 2012). New chemical entities were developed based on the idea of modality-specific antagonism. Such a compound, NEO6860, which is being advanced by NEOMED, a public-private organization in Montreal developing early-stage drug discovery projects, is now entering clinical study [download PDF below].
In vitro data demonstrated that NEO6860 blocks capsaicin activation of the human TRPV1 channel but does not inhibit heat- or pH-evoked responses. In primate dorsal root ganglion (DRG) neurons, NEO6860 was found to selectively antagonize capsaicin-evoked currents, sparing the heat response, and did not increase heat thresholds of primate unmyelinated C-fibers.
Hopefully, this compound will provide the first human test of the modality-specific TRPV1 blocker hypothesis, and can avoid hyperthermia and burn injury side effects and provide validation of preclinical data supporting this view. Most importantly, the compound will hopefully be shown to maintain analgesic properties.