Gallo, MariaMoreno Guillén, EstefaníaDefaus, SiraOrtega-Alvaro, AntonioGonzalez, AngelRobledo, PatriciaCavaco, MarcoNeves, VeraCastanho, Miguel A.R.B.Casadó, VicentPardo, LeonardoMaldonado, RafaelAndreu, David2021-06-162022-04-222021-04-220022-2623https://hdl.handle.net/2445/178408The 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.12 p.application/pdfeng(c) American Chemical Society , 2021CànnabisTractament del dolorPèptidsCannabisPain treatmentPeptidesinfo:eu-repo/semantics/article7119162021-06-16info:eu-repo/semantics/openAccess