A novel Scaffold for Mode-Selective Inhibition of TRPV1

Pain is estimated to affect about 30% of the world’s population and treatment is challenging because of issues with addiction and withdrawal which accompany many current analgesics. Human TRPV1 is a widely expressed nociceptor and is a desirable target to modulate diverse human pathophysiologies, including pain, obesity, and diabetes, among others. As an analgesic target, human TRPV1 is particularly attractive because it is non-addictive. However, attempts at inhibiting TRPV1-mediated pain pathways have resulted in issues with thermosensing and body temperature misregulation.

• Mode-specific inhibition of TRPV1
  • Analgesics
  • Diabetes treatment
  • Obesity treatment
• Could be used to isolate, detect and screen for novel TRPV1 compounds with higher binding and fewer off-target effects

• Limits the crosstalk with TRPV1 activation modes that give rise to clinical liabilities
• Influences dynamics in a way that leads to mode-specific inhibition
• This scaffold can be used to develop next generation mode-specific TRPV1 inhibitors
• The chemical scaffold mitigates thermogenic and thermosensing on-target effects
  • Outside-out patch-clamp electrophysiology measurements have demonstrated that thermosensitivity is reduced by nearly half (from 110 ± 4 kcal/mol to 48 ± 2kcal/mol)

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