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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Cannabinoid CB1 receptor (CB1R) activation by Δ9-tetrahydrocannabinol (THC) induces analgesia but also cognitive impairment.
  • This impairment is mediated by the serotonin 5HT2A receptor (5HT2AR) within a CB1R-5HT2AR heteromer.
  • A significant drawback for therapeutic applications of cannabinoids is the associated cognitive side effects.

Purpose of the Study:

  • To optimize peptide prototypes that modulate the CB1R-5HT2AR heteromer.
  • To develop drug-like leads that retain the ability to avert THC-induced cognitive impairment while preserving analgesia.
  • To identify an orally active peptide candidate for effective and safe cannabis-based pain management.

Main Methods:

  • Peptides mimicking CB1R transmembrane helices 5 and 6, fused to a cell-penetrating sequence (CPP), were initially designed.
  • Prototypes were optimized by shortening TM5, TM6, and CPP sequences.
  • Extensive sequence remodeling was performed to enhance protease resistance and blood-brain barrier penetration.

Main Results:

  • Optimized peptides successfully disturbed the CB1R-5HT2AR heteromer without losing efficacy.
  • The modified peptides demonstrated protease resistance and improved blood-brain barrier penetration.
  • An orally active 16-residue peptide was identified, preserving THC-induced analgesia.

Conclusions:

  • Shortened and remodeled peptides maintain the ability to modulate CB1R-5HT2AR heteromers.
  • The optimized peptide candidate is orally bioavailable and suitable for managing pain.
  • This represents a significant advancement in developing safer cannabinoid-based therapeutics for pain relief.