Chemistry and biological activities of N,N-dimethylaminoethyl acrylate, a choline acetyltransferase inhibitor.

N,N-Dimethylaminoethyl acrylate (acryl-DMA) was synthesized as a tertiary nitrogen choline acetyltransferase (ChAc) inhibitor which would be able to penetrate biological membranes to inhibit ChAc in the nerve terminal. The synthesis from dimethylaminoethanol and acrylyl chloride was described and the hydration with times in an aqueous medium measured by NMR spectroscopy was presented. The autohydrolysis in water was found to be 1.75 x 10(-8) mol/min at pH 7.4 and 5.0 mM concentration. The enzymatic hydrolysis was unaffected by cholinesterases. Acryl-DMA was capable of inhibiting ChAc extracted from rat brain with I50 of 5.02 x 10(-4) M. The inhibition was reversible and displayed uncompetitive kinetics with respect to both substrates, choline and acetyl-CoA. Neither the hydrolysis nor the hydration products of acryl-DMA could inhibit ChAc. Although acryl-DMA was hydrated rapidly and completely within 1 hr at high pH (9.0), the time course of inhibition ability of acryl-DMA in aqueous medium at physiological pH was found to decrease rather slowly and by 36% in 1 hr, indicating that acryl-DMA can survive from hydration at physiological pH. Acryl-DMA was also tested for its ability to block electrically induced muscle contractions in both isolated skeletal and smooth nerve-muscle preparations. The ED50's obtained were less than 5 x 10(-4) M in both cases.