Small Molecule TRP Modulators

Despite their initial irritant properties, capsaicin and related TRPVI agonists ultimately reduce sensitivity to painful stimuli by desensitizing the receptor. 

Recent reports have emerged of several TRPV1 antagonists possessing a biaryl amide (14-16), urea (17), or urea isostere (18-20) scaffolds. Bicyclic derivatives 14-16 block capsaicin- or pH-stimulated calcium influx in FLIPR-based assays 

Two of the best-known modulators of TRPM8 activity are menthol (31) and icilin (32). Menthol is effective at inducing calcium influx at 10-100 pM, while icilin is effective in the 0.1-1 pM range. While the residues responsible for activation of TRPM8 by menthol have been identified [57], recent results demonstrate that the activation of TRPM8 by icilin and cold, but not menthol, is modulated by intracellular pH in the physiological range [58]. 

There has been a steady increase in the fundamental understanding of the roles of TRP channels in human conditions. However, more selective modulators of many of these channels are required to fully understand their role in physiological and pathophysiological conditions. 

Case History JANUVIA (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes 

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