Acetylcholine conformational restriction

Mullen G, Napier J, Balestra M, DeCory T, Hale G, et al. 2000. (-) -Spiro [ 1 -azabicyclo [2.2.2] octane-3,5 -oxazolidin-2 -one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha-7 nicotinic acetylcholine receptor. J Med Chem 43 4045-4050. 

The principle of conformational restriction was first applied to characterize the bioactive conformation of acetyl choline acting at the muscarinic and nicotinic receptors. Conformational restriction has been applied to many other small ligands (e.g. see reviews by Martin-Smith et al., Portogh-ese, Mutschler and Lambrecht, and Casy et but the work on acetylcholine analogs exemplifies the necessary ideas and techniques required to understand the general approach, as well as its strengths and limitations, when applied to small molecules. 

A ring system that is able to restrict conformational flexibility while minimizing additional bulk is cyclopropane. As a strained system, its angles differ from the standard 60° and 180° possibilities with cyclohexane. The (+)-trans cyclopropane analogue (9.26) does show muscarinic activity comparable to acetylcholine (Figure 9.13). The dihedral angle between the ester and ammonium group is approximately 145°. The (—)-trans enantiomer and both... 

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