Pharmacological studies of N,N-dimethylaminoethyl chloroacetate and N,N-dimethylaminoethyl acrylate as inhibitors of choline acetyltransferase in isolated skeletal and smooth muscle preparations.
Two tertiary amine esters, N,N-dimethylaminoethyl chloroacetate (Cl-DMA) and N,N-dimethylaminoethyl acrylate (acryl-DMA), which have recently been shown to be inhibitors of choline acetyltransferase (ChAc) were investigated to determine their actions in isolated skeletal and smooth muscle preparations. Both compounds caused neuromuscular blockade in indirectly stimulated nerve-muscle preparations (ED50 values of Cl-DMA were 6.9 -42.0 X 10(-4) M and those of acryl-DMA were 1.2-5.8 X 10(-4) M). The blockade was completely or partially reversible after drug washout. A comparison of the ED50 values for neuromuscular blockade with the ID50 values for ChAc inhibition suggested that the acryl-DMA compound might not cause neuromuscular blockade via ChAc inhibition because the potency ratios (ED50/ID50) of Cl-DMA were higher than 1, whereas those of acryl-DMA were equal to or lower than 1. This was borne out by further experiments on isolated neuromuscular preparations which showed that the site of action for acryl-DMA was post-junctional, whereas that for Cl-DMA was prejunctional. In addition, the weak stimulating properties of Cl-DMA and acryl-DMA were investigated in isolated skeletal and smooth muscle. Cl-DMA was shown to be a partial cholinergic agonist, whereas acryl-DMA was a nonspecific stimulant not involving cholinergic receptors. Although both Cl-DMA and acryl-DMA are inhibitors of ChAc, only Cl-DMA appears to have sufficient specificity for use as a possible ChAc inhibitor in vivo.
D000085:Acetates / Q000494:pharmacology*; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002645:Chickens; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000201:enzymology*; D009132:Muscles / Q000201:enzymology*; D009431:Neural Conduction / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D011894:Rana pipiens; D051381:Rats
D000085:Acetates; D000179:Acrylates; D000123:Acetyltransferases; D002795:Choline O-Acetyltransferase