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Audio Interview

Unlocking a cryptic pocket: a new approach to safer pain relief

Published on July 30, 2026   8 min

Other Talks in the Playlist: Research Interviews

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Interviewer: We're joined today by Susruta Majumdar and Vipin Rangari to discuss their recent Nature paper, which details the design of a peripherally restricted CB1 agonist that offers potent pain relief without the central side effects or tolerance that are typically associated with cannabinoid-based therapies. Susruta and Vipin, thank you so much for joining us today. What inspired your team to explore the cryptic pocket within the CB1 receptor, and how did this approach differ from traditional CB1-targeted drug development? Dr. Rangari: Thank you for this question. We wanted to develop peripheral cannabinoid agonist analgesics with reduced tolerance to combat psychoactive or strong stoning effects seen in humans. So we thought this could be achieved in two ways; put a charge at the tail end of the molecule and go after blunting arrestin response, which mediates tolerance. So our lab has previously shown that targeting aspartate D250 site with charged agonists at opioid receptor can lead to blunted arrestin response, and this aspartate D250 site is conserved across 330 Class A GPCRs. So taking cues from this, we delved into CB1 receptor which is another potential target for pain relief. But in a molecular dynamics simulation study, we observed this aspartate D250 site is present in an allosteric site, which is blocked by toggle switch residues, phenylalanine and tryptophan, in the cryptic pocket. Our MD studies also showed that this cryptic pocket

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