Quantitative structure-activity studies of neurotoxic acrylamide analogs

Abstract Acrylamide is an important commodity chemical to produce polymers used in various forms for industrial, scientific and public purposes. The monomer has been known to cause neurotoxic symptoms in test animals and human beings under chronic exposures. We measured the neurotoxic potency for a number of structurally related, mostly, N-substituted analogs using mice. We also evaluated related bioactivities such as acute toxicity to mice, cytotoxicity to cultured cells originated from murine nervous systems, inhibitory activities to rat-brain glycolytic enzyme preparations and in vitro metabolic susceptibilities to mouse-liver enzyme preparations. The variations in each toxicity or bioactivity index among analogs were quantitatively examined with the use of physicochemical molecular and submolecular parameters by regression analyses. The physical-organic reactivities of acrylamide analogs as the Michael addition substrates and quenching agents of fluorescence from the aromatic amino acids were also examined extrathermodynamically and used as molecular parameters for the quantitative analyses whenever relevant. The comparative overview of quantitative structure-activity formulations led us to hypothesize that electronic and steric properties and hydrogen-bonding factors of the amide moiety are operating together to govern variations in the neurotoxic potency.