Acetylcholine quaternary ammonium group

Acetylcholine is an ester of choline and acetic acid, the prototype for a small family of choline ester compounds. The choline moiety of ACh contains a quaternary ammonium group that gives ACh a permanent positive charge, making it very hydrophilic and membrane impermeant. 

Acetylcholinesterase (AChE) deesterifies the neurotransmitter acetylcholine (ACh). AChE belongs to a group of enzymes considered serine esterases and has a mechanism similar to that of chymotrypsin. AChE has an anionic binding site that attracts the positively charged quaternary ammonium group of ACh. The serine then attacks and cleaves the ester.910... 

The detailed mechanism by which AChE and BChE hydrolyze ACh has been the subject of much research, especially since the crystal structure of the Torpedo califomica AChE was elucidated by Sussman et al. in 1991 [12]. (Reviews of these enzymes and their interactions can be found in Refs. [5,13]). This mechanism will be described here only briefly, as an introduction to the reaction of the enzyme with carbamates. The active site of AChE is located at the bottom of a 20 A-deep gorge, where acetylcholine fits in by attachment of the quaternary ammonium group to the so-called anionic site (mainly through cation interaction with the n electrons of Trp84), and by dipole interactions between the ester group and Ser200 at the esteratic site . 

Rosenfield, R. E., and Murray-Rust, P. Analysis of the atomic environment of quaternary ammonium groups in crystal structures, using computerized data retrieval and interactive graphics modeling acetylcholine-receptor interactions. J. Amer. Chem. Soc. 104, 5427-5430 (1982). 

Curare-type drugs containing essentially a bulky strueture together with a minimum of one quaternary ammonium group, complete with acetylcholine thereby preventing a free access to the cholinergic receptors. 

Nerve cells interact with other nerve cells or with muscles at junctions, or gaps, called synapses. Nerve impulses are carried across the synaptic gap by chemical compounds called neurotransmitters. Acetylcholine (see the following reaction) is an important neurotransmitter at neuromuscular synapses called cholinergic synapses. Acetylcholine contains a quaternary ammonium group. Being small and ionic, acetylcholine is highly soluble in water and highly diffusible, qualities that suit its role as a neurotransmitter. Acetylcholine molecules are released by the presynaptic membrane in the neuron in packets of about 10" molecules. The packet of molecules then diffuses across the synaptic gap. 

A study of the interaction of acetylcholine with serum cholinesterase, using NMR claimed that the rate of initial line broadening was greater for the quaternary ammonium group than for the acetyl group. 

Solutions in acetone-dg of known concentration close to 3 x 10 mol L in choline or acetylcholine perchlorates were prepared and used as solvents for calixarene salts so as to obtain series of solutions in which the host guest (calixarene quaternary ammonium group) ratio varied between 0 and 2.00. Proton chemical shifts were measured for the trimethylammonium resonances of all solutions using a Bmker WP80 instmment. Inclusion equilibrium constants were determined from nonlinear least-squares fitting of the chemical shift vs. host guest ratio curves. 

The above speculation [21] may be extended to include the related quaternary ammonium compounds such as xylocholine (XXXIX). It is probable that the volumes of the guanidinium ion and the trimethylammonium group are similar. The ionic radius of the guanidinium ion (IX) is about 3A the ionic radius of the tetramethylammonium ion has been estimated [300] to be 3-4A, although rather smaller values have also been proposed [301-303]. Crystallographic analyses of muscarine iodide [304], choline chloride [305] and acetylcholine bromide [306] have revealed that the carbon to nitrogen distance is about l-SA, and that a hydrogen bond (C-H-0 distance 2-87-3 07A) exists in the crystals of these compounds. 

Curare-like muscle relaxants act by blocking acetylcholine receptor sites, thus eliminating transmission of nerve impulses at the neuromuscular junction. There are two acetylcholine-like groupings in the molecules, and the drugs, therefore, probably span and block several receptor sites. The neurotransmitter acetylcholine is also a quaternary ammonium compound. The natural material present in curare is tubocurarine, a complex alkaloid that is a mono-quaternary salt. Under physiological conditions, the tertiary amine will be almost completely protonated (see Section 4.9), and the compound will similarly possess two positively charged centres. 

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