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Carbamoylcholine bromide

+ 178

Acetylthiocholine bromide

+ 171

Acetyl-(Ra, Sß)-dimethylcholine iodide (erythro)

+76

From Shefter, E.: Structural variations in cholinergic legends. In Triggle, D. J., Moran, J. F., and Barnard, E. A. (eds.). Cholinergic Ligand Interactions. New York, Academic Press, 1971, pp. 87-89.

From Shefter, E.: Structural variations in cholinergic legends. In Triggle, D. J., Moran, J. F., and Barnard, E. A. (eds.). Cholinergic Ligand Interactions. New York, Academic Press, 1971, pp. 87-89.

because of the large size of at least one molecule. For the first time, the conformation of a neurotransmitter has been determined for a molecule in the bound state. ACh is transformed from the gauche conformation in the free state to a nearly trans conformation when bound to the nicotinic receptor.32 The active conformation of muscarinic agonists on their receptor has a dihedral angle of r2 between 110° and 117°.33

The parasympathomimetic effects of muscarine were first reported in 1869,34 but its structure was not elucidated until 1957.35 Muscarine has four geometric isomers: muscarine, epimuscarine, allomuscarine, and epiallomuscarine (Fig. 17.10). None has a center or plane of symmetry. Each geometric isomer can exist as an enantiomeric pair. The activity of muscarine, a nonselective muscarinic receptor agonist, resides primarily in the naturally occurring (+ )-muscarine enantiomer.

It is essentially free of nicotinic activity and apparently has the optimal stereochemistry to act on the muscarinic receptor subtypes. Synthetic molecules with a substituent on the carbon atom that corresponds to the [ carbon of ACh also show great differences in muscarinic activity between their isomers. Acetyl-(+)-(S)-[-methylcholine, (+)-cis-(2S)-methyl-(4R)-trimethylammonium-1,3-dioxolane, (+)-trans-(1S,2S)-ace-toxycyclopropyltrimethylammonium, and naturally occurring (+)-(2S,3R,5S)-muscarine are more potent than their enan-tiomers and have very high ratios of activity between the (S)- and (R)-isomer (Table 17.3). A similar observation may be made of (+)-acetyl-(S)-[-methylcholine, (+)-cis-(2S)-methyl-(4R)-trimethylammonium-1,3-dioxolane, and (+)-trans-(1S,2S)-acetoxycyclopropyltrimethylammonium, all of

Figure 17.9

ch3 h

Gauche conformers of methacholine.

Figure 17.8 • ACh torsion angles.

Figure 17.9

ch3 h

Gauche conformers of methacholine.

Figure 17.10 • Geometric isomers of muscarine.

Figure 17.11 • Hypothetical structure of the muscarinic receptor.

Figure 17.10 • Geometric isomers of muscarine.

Figure 17.11 • Hypothetical structure of the muscarinic receptor.

which have an (s) configuration at the carbon atom that corresponds to the [ carbon of ACh. Each of these active muscarinic molecules may be deployed on the receptor in the same manner as ACh and (+)-muscarine. Their (s)/(r) ratios (Table 17.3) show the greatest stereoselectivity of the muscarinic receptor in guinea pig ileum for the configuration at the carbon adjacent to the ester group. In contrast, the nicotinic receptors are not considered as highly stereoselective as their muscarinic counterparts.

c/'s-2-Methyl-4-trimethylammonium-1l3-dioxolane

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