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

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 10 Pg. 6937-6948 (05 27 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33887904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Cannabinoids
• Peptides
• Receptor, Cannabinoid, CB1
• Receptor, Serotonin, 5-HT2A

Topics

• Administration, Oral
• Amino Acid Sequence
• Analgesics (chemistry, metabolism, pharmacology, therapeutic use)
• Animals
• Behavior, Animal (drug effects)
• Binding Sites
• Blood-Brain Barrier (drug effects, metabolism)
• Cannabinoids (chemistry, pharmacology)
• Cannabis (chemistry, metabolism)
• Dimerization
• Mice
• Mice, Inbred ICR
• Molecular Dynamics Simulation
• Pain (drug therapy, pathology)
• Peptides (chemistry, metabolism, pharmacology, therapeutic use)
• Receptor, Cannabinoid, CB1 (agonists, metabolism)
• Receptor, Serotonin, 5-HT2A (chemistry, metabolism)