-AMINO FATTY ACID ESTERS OF CHOLINE: INTERACTION WITH CHOLINESTERASES AND NEUROMUSCULAR ACTIVITY IN MAN

¹ Departments of Anesthesiology, Montefiore Hospital and Medical Center, and Albert Einstein College of Medicine, New York, N. Y.

The interaction of five fatty acid esters and 17 -amino substituted fatty acids esters of choline with human plasma cholinesterase (PChE) and red cell cholinesterase (RChE) was investigated. The general structural formula of the compounds was R—(CH₂)_n—CO—O—(CH₂)₂—N⁺(CH₃)₃.

None of the compounds tested was hydrolyzed by RChE. Of the nonsubstituted compounds (R = H), propionylcholine (n = 2) and butyrylcholine (n = 3) were hydrolyzed most rapidly by PChE. The -amino-substituted derivatives (R = NH₂) were hydrolyzed by PChE considerably more slowly than the nonsubstituted compounds. With the amino-substituted compounds, the maximum hydrolysis rate by PChE was observed with 7-aminoheptanoylcholine (n = 6). Substitution of one or both hydrogens in the amino group by methyl radicals or quaternization of the amino nitrogen by substitution of three methyl radicals resulted in a progressive decrease of the hydrolysis rate by PChE. Neither the nonsubstituted nor the amino-substituted choline esters inhibited the hydrolysis of ACh by PChE. The inhibitory effect of both the nonsubstituted and the amino-substituted compounds on RChE increased with increasing values of n. Some of the monomethyl-and dimethylamino and trimethylammonium derivatives inhibited the hydrolysis of ACh, not only by RChE, but also by PChE. Of the methylamino substituted compounds, the dimethyl derivatives were the most potent inhibitors of both RChE and PChE. The inhibitory effect of the dimethyl derivatives on RChE increased with increasing values of n. The maximum effect for PChE, however, was obtained with 5-dimethylaminovalerylcholine (n = 4) and 6-dimethylaminocaproylcholine (n = 5).

The neuromuscular blocking action of the three compounds, 7-aminoheptanoylcholine (AHCh), 6-dimethylaminocaproylcholine (DACCh) and 6-trimethylammoniumcaproylcholine (TACCh), which are hydrolyzed by human PChE but not by cat PChE, and which had similar potency and duration of action in cats, was investigated in lightly anesthetized human subjects. In man, in contrast to the cat, there was a wide variation in the neuromuscular effects of AHCh, DACCh, and TACCh. The potency and duration of action of these compounds varied inversely with their enzymatic hydrolysis rate by human PChE. The neuromuscular effects of TACCh and succinylcholine (SCh), hydrolyzed by PChE at about the same rate, were almost identical. Similarly to SCh, the intensity and duration of the neuromuscular effect of ARCh, DACCh, and TACCh were markedly increased after the inhibition of PChE by hexafluorenium.