Current drug design has largely overlooked that function of G-protein coupled receptors (GPCRs) can differ between healthy and pathological microenvironments. The success of pH-dependent opioid ligands illustrates the therapeutic potential of exploiting such conditions. Redox changes may represent another regulatory component, but functional and in vivo evidence is still lacking. The consideration of microenvironmental factors may enable the development of safer, peripherally acting analgesics and refine GPCR-targeted drug design.
Detzner et al. (2026) studied this question.