A cryptic pocket in CB1 drives peripheral and functional selectivity.

Area of Science:

• Pharmacology
• Neuroscience
• Medicinal Chemistry

Background:

• The opioid overdose epidemic necessitates safer chronic pain treatments.
• Cannabinoid receptor type 1 (CB1) agonists show promise but are limited by psychoactivity and tolerance.
• Developing peripherally restricted CB1 agonists is crucial for effective pain management.

Purpose of the Study:

• To design and develop novel, peripherally restricted CB1 agonists with reduced psychoactivity and tolerance.
• To investigate the molecular mechanism underlying biased signaling and peripheral selectivity.
• To evaluate the analgesic efficacy and safety profile of novel CB1 agonists in preclinical pain models.

Main Methods:

• Computational design of positively charged CB1 agonists targeting a cryptic pocket.
• Molecular dynamics simulations to identify binding modes and receptor interactions.
• Structure determination and pharmacological assays to validate ligand binding and signaling.
• In vivo assessment of analgesic efficacy and central side effects in mouse pain models.

Main Results:

• Designed peripherally restricted CB1 agonists, including VIP36, by targeting a cryptic pocket.
• VIP36 demonstrated significant analgesic efficacy in three mouse pain models.
• VIP36 showed a 100-fold dose separation between efficacy and central side effects.
• VIP36 exhibited limited analgesic tolerance and acted via peripheral CB1 receptors.

Conclusions:

• Targeting cryptic pockets in G-protein-coupled receptors can yield peripherally selective, biased agonists.
• This strategy enhances in vivo pharmacology and reduces adverse effects for chronic pain treatment.
• The findings have broad implications for drug design targeting G-protein-coupled receptors and managing chronic pain.