Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects

The activation of cannabinoid CB1 receptors (CB1R) by ?9-tetrahydrocannabinol (THC), the main component Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via serotonin 5HT2A receptor (5HT2AR), a CB1R–5HT2AR heteromer, posing serious drawback for therapeutic use. We have shown that peptides reproducing transmembrane (TM) helices 5 and 6, fused to cell-penetrating sequence (CPP), can alter structure heteromer avert THC while preserving Here, we report optimization these prototypes into drug-like leads (i) shortening TM5, TM6, CPP sequences, without losing ability disturb (ii) extensive remodeling achieve protease resistance blood–brain barrier penetration. Our efforts culminated in identification an ideal candidate cannabis-based pain management, orally active 16-residue peptide THC-induced