Papers of the Week

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