Quaternary amines acetylcholine receptors

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. 

Reserpine acts on the dopamine transporter to cause release of the amine, so that free dopamine accumulates extracellularly. The binding appears to be non-covalent [247, 263]. (-)-Cathinone acts similarly [264]. Nicotine and, even more, some quaternary, N-methylated products of nicotine metabolism, inhibit dopamine uptake. This may help to explain why smoking relieves some symptoms of Parkinsonism [265, 266, 267]. In another way, nicotine acting on certain acetylcholine receptors evokes release of dopamine from rat striatal cells [268], Veratridine has a similar effect [142]. 

Although this story proved a little too complex to be widely appreciated, and few were inclined to generalize from the evidence, the topic acquired a new facet when Ing (1936) published his much-quoted review. In this he pointed out that the alkaloid tubocurarine (2.6), which blocks neuromuscular transmission (see Section 2.0), must do so by competing with acetylcholine for a receptor in voluntary muscle (both substances are quaternary amines). In addition, Ing postulated that the somewhat weaker curariform action of innumerable quaternary ammonium, phosphonium, arsonium, stibonium, and sulphonium salts arose from their competition with acetylcholine (Ing, 1936). (For further reading on the physiological... 

The cationic head of acetylcholine. It is useful to pause here and compare acetylcholine cations with inorganic cations likely to be present at the receptor surface. Whereas potassium has a stimulant action on all of the muscle, the action of acetylcholine is normally confined to the small end-plate region. The shielding effect of the alkyl-groups (on the nitrogen atom in a quaternary amine) ensures that the ion is virtually anhydrous in aqueous solution (Robinson and Stokes, 1959). Thus the effective ionic radius in solution may be taken as the same as the radius obtained from X-ray crystallography. It is seen from Table 13.1 that the tetramethylam-monium ions has a radius of 2.41 A, and this must also be the radius of the cationic head of acetylcholine. 

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