Safety Considerations

Although TRPA1 is expressed primarily in sensory neurons, it is also present in a variety of other tissues (bladder, the GI tract, various brain regions, skin, lung, cardiomyocytes, cardiac fibroblasts, and pancreas), and hence consideration of potential safety side effects resulting from on-target pharmacology is an important aspect of any TRPA1 programme [2,13]. TRPA1 KO mice appear to have normal reproduction and auditory function [21,23], although physical hyperactivity was recently reported [88].

As outlined earlier, the effect of ablating TRPA1 on CNS function was recently investigated by Lee et al. In this study, TRPA1 KO mice appear to have enhanced hippocampal function although motor function deficits were seen [82]. Astrocytes contribute to the formation and function of synapses throughout the brain. Recent work by Shigetomi et al. has shown that astrocytic TRPA1 channels regulate miniature inhibitory postsynaptic currents through GAT-3. In this work, mechanistic evaluations in brain slices showed that decreases in astrocyte resting Ca2+ concentrations, mediated by TRPA1 channels, decreased interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3 and elevating extracellular GABA [89]. In addition, TRPA1 modulates glycinergic transmission in the synapses of the medullary dorsal horn neurons, enhances glutamate release in the presynaptic terminals of magnocellular neurosecretory cells, and is linked with activation of the cannabinoid receptor CB1 in the hippocampus [13,90]. The (patho)physiological impact of chronic TRPA1 inhibition on CNS function is still to be fully elucidated; however, small molecules with a CNS-sparing distribution profile may offer a potentially safer side-effect profile for peripheral mechanisms such as TRPA1-mediated inflammatory pain.

A theoretical risk exists in the development ofTRPA1 antagonists in that TRPA1 is thought to be a detector of harmful irritants or environmental conditions [62,63]. Airway exposure to chlorine results in reduced breathing frequency and increased end expiratory pause in wild-type mice, but such protective reflexes are absent in TRPA1 KO mice [62]. The extent to which TRPA1 antagonists cause deficits in sensing and avoiding irritants in humans would be an important consideration during any TRPA1 clinical development programme.

Studies conflict on the potential role of TRPA1 in thermosensation and thermoregulation in mammals. In one study, TRPA1 KO mice displayed a reduced sensitivity to cold, as measured by paw withdrawal from a 0°C plate or paw shaking in response to acetone-induced cooling [23]. In another study, TRPA1 KO mice were shown to have the same thermogenic response to cold as their wild-type littermates. In the same study the effects of pharmacological blockade in rats were investigated, with TRPA1 antagonists showing no effect on thermoregulatory responses [91]. The effect of an orally administered TRPA1 antagonist on thermosensation was investigated by researchers at Novartis [27]. In this study, naive mice, when administered with Novartis compound 31 (39), demonstrated a reduced sensitivity to a cold (—5°C) surface in a dose-dependent manner, and of a similar magnitude to that seen in TRPA1 KO mice [23]. The ability of‘compound 31’ to affect body temperature was also investigated, and ‘compound 31’ did not alter body temperature despite the effect observed on noxious cold sensation.

TRPA1 agonists have been shown to delay gastric emptying in rats [92], although it is not clear as to whether TRPA1 antagonists would have deleterious effects on gut motility. Beta islet cells of the pancreas have been shown to express TRPA1. TRPA1 agonists stimulate insulin release in pancreatic beta cells, an effect that is inhibited by TRPA1 antagonists and by RNA interference [93]. The effect of chronic administration ofTRPA1 antagonists on insulin levels has not been reported.

There is a proposed role for TRPA1 in ultraviolet (UV)-induced melanin production in human melanocytes [94]. The findings from Bellono et al. demonstrate that it is involved in UVA-induced early melanin synthesis. TRPA1 inhibition may not be a significant safety liability in humans with respect to UV radiation (UVR) exposure and melanin photoprotection given that involvement of TRPA1 in pigmentation appears to be only in the early immediate pigment darkening (IPD) phase (1—24 h) and this phase is not thought to be a major component of photoprotection. In addition, multiple pathways modulate melanocyte function with early melanogenesis only one component of this modulation. Furthermore, TRPA1 inhibition accounts for only an approximately 60% decrease in UVR-induced Ca2+ flux and around an 80% decrease in UVR-induced melanin increase in human epidermal melanocytes, suggesting that additional (potentially compensatory) mechanisms for Ca2+ influx and melanin increase may exist.

Although a limited number of compounds have so far progressed to the clinic, significant adverse events have not been reported. This may suggest that TRPA1 antagonism is not associated with significant safety issues, although close attention will be paid to additional clinical reports.

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