Cannabidiphorol (CBDP) interactions with Cannabinoid Receptor 1 (CB1R) as a strong negative allosteric modulator

Building on the 2019 discovery of cannabidiphorol (CBDP), a heptyl analogue of CBD isolated from the FM2 chemovar of Cannabis sativa [ 1 ], and its structural resemblance to known CB1R allosteric modulators [ 2 ], this study explored CBDP’s potential as a negative allosteric modulator (NAM) of CB1R. Computational modeling pinpointed two likely allosteric binding sites for CBDP, like CBD: the established ORG27569 site and a newly identified intracellular site near TMHs 1, 2, 6, 7, and helix 8. Functional assays and mutagenesis studies confirmed that both compounds interact with this intracellular site, revealing crucial residues for receptor modulation. Importantly, in vivo co-administration experiments in mice showed that CBDP effectively counteracted Δ 9 -THC-induced memory impairment while preserving its antinociceptive effects. These results establish CBDP as a novel CB1R NAM targeting an intracellular allosteric site, offering a promising avenue for mitigating the cognitive side effects of Δ 9 -THC in cannabinoid-based therapies. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany