Do para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity?
We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.
Accelerator mass spectrometry analysis has an excellent correlation with biodistribution measurements using gamma counter. Our results suggest that the combination of AMS and PET can act as a complementary approach to accelerate drug development.