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

The
activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the
main component of Cannabis sativa,
induces analgesia. CB1R activation, however, also causes
cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R–5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic
use. We have shown that peptides reproducing CB1R transmembrane
(TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP),
can alter the structure of the CB1R–5HT2AR 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 CB1R–5HT2AR 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.