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

Maria Gallo, Estefanía Moreno, Sira Defaus, Antonio Ortega-Alvaro, Angel Gonzalez, Patricia Robledo, Marco Cavaco, Vera Neves, Miguel A R B Castanho, Vicent Casadó, Leonardo Pardo, Rafael Maldonado, David Andreu

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)6937-6948
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number10
Publication statusPublished - 27 May 2021


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