Acetylcholine cationic head

It is important to determine whether or not each substituent parameter is an independent variable. If a considerable correlation exists between two parameters in a set of compounds, it is often difficult to evaluate the quality of structure—activity correlations. The data in Table II are for the muscarine-like activity of acetylcholine analogs measured by the blood pressure descent of cats (55). The effect of cationic head structure has been analyzed using physicochemical parameters of the N substituents (II). 

The distance between the ester moiety and the cationic head of acetylcholine seems to be critical. Acetoxytrimethylammonium (27), com-... 

Whereas the radius of every inorganic ion, in the anhydrous state, is well established, those of low mass are strongly hydrated in solution so that their effective radius is much greater. Just how much greater cannot be said because an exact method for measurement is lacking. However, the figures for Li and Na" " in the last column of Table 12.2 are indicative. The cationic head is the widest part of the acetylcholine molecule. What happens if it is made wider First, let us note the acetylcholine-like effect of simple aliphatic quaternary amines. These have only a feeble action on muscarinic sites, although their action on nicotinic sites is considerable (see below). Tetramethylammonium salts, for example, have only about one-thousandth of the activity of acetyl-... 

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. 

Ganglion-blocking activity in the polymethylene iwtrimethyl-ammonium series is maximal when the two cationic heads are separated by five or six methylene-groups (Baton and Zaimis, 1949). Hexamethonium (7.24, n = 6), the most efficient ganglion-blocker in this series, competes with acetylcholine without causing any depolarization of the receptor (Baton and Berry, 1953). 

A possibly serious defect in the design of compounds such as the piperidinium (222), the morpholinium (223), the tropines (226) and (227), and the decahydroquinoliniums (228) is that these molecules do not bear the trimethylammonium cation characteristic of acetylcholine, but rather the quaternary head is a part of a ring system. It was indicated previously that incorporation of the nitrogen atom of acetylcholine itself into a ring is detrimental to cholinergic activity and potency. 

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