This intracellular strategy could reduce side effects and improve efficacy for chronic pain and addiction by activating favorable pathways while silencing toxic responses.

A new GPCR targeting strategy uses intracellular binding sites on neurotensin receptor 1 to selectively activate or inhibit specific signaling pathways, rather than engaging traditional extracellular sites.

Leadership emphasizes that this approach provides nuanced GPCR ‘volume control,’ enabling rational design of next-generation medicines.

The team’s method aims for precise, pathway-specific therapeutic effects by modulating intracellular allosteric sites.

The work broadens the druggable GPCR landscape, pursuing safer, smarter medicines by steering specific signaling outcomes rather than global receptor activation or inhibition.

This advances precision pharmacology, moving GPCR modulation toward context-dependent signaling tuning and potential personalized therapies with improved safety.

By exploiting an intracellular pocket, the approach enhances beneficial G protein interactions while dampening harmful ones, enabling finer control over signaling than conventional ligands.

Researchers from the University of Minnesota Medical School, with Sanford Burnham Prebys chemists, describe using intracellularly binding compounds—molecular bumpers and molecular glues—to rewire GPCR signaling.

The study, published in Nature on October 22, 2025, was a collaboration with SBP researchers and received support from NIH, NIAAA, DoD, and university and Japanese research agencies.

Computational modeling guided the design of diverse compounds that produce distinct signaling profiles, showing that changes in chemical structure predictably steer pathway engagement.

Using neurotensin receptor 1 as a model, the researchers merged computational modeling with pharmacology to craft compounds that shift G protein coupling preferences and downstream signaling.

As molecular glues, the compounds foster beneficial interactions with certain partners, while as molecular bumpers they block others, effectively changing cellular signaling messages rather than simply scaling activity up or down.