Acetylcholine, conformational flexibility

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... 

It lias been proposed that the conformational flexibility of most open-chain nearohormoncs. such as acetylcholine, epinephrine. serotonin, histamine, and related physiologically active biomolecules, permits multiple biological effects to he produced by each molecule, by virtue of their ability to. 

The first application of all-valence electron MO theory to predict the conformation of a neurotransmitter was reported in 1967 on acetylcholine (8). Using EHT, the conformation of acetylcholine was predicted to assume an approximately gauche relationship between the nitrogen and ether oxygen atoms. This is in agreement with experimental evidence derived from aqueous solution NMR studies (9). Some flexibility was predicted for the CO-O bond so that the dimensions between the heteroatoms were predicted as shown in Figure 1. 

Schueler (267) suggested that the muscarinic and nicotinic effects of acetylcholine are mediated by different conformers of the flexible molecule, and he evaluated structures ( )-(222)("transoid")and (223)("cisoid")as examples of analogs of conformational extremes of acetylcholine. 

A 3D model of the receptor binding site has been worked out with the aid of conformationally restrained analogues of acetylcholine. Acetylcholine itself has no conformational restraints. It is a straight-chain molecule in which bond rotation along the length of its chain can lead to numerous possible conformations (or shapes). Thus, it is impossible to know exactly the 3D shape of the receptor site from considering acetylcholine alone. In the past, it was assumed that a flexible neurotransmitter such as acetylcholine would interact with its receptor in its most stable conformation. In the case of acetylcholine, that would be the conformation represented by the sawhorse and Newman projections shown in Fig. 11.12. 

In order to establish the active conformation of a flexible neurotransmitter (the conformation taken up by the neurotransmitter once it is bound to the receptor), it is necessary to study structures which contain locked conformations of acetylcholine within their structures. Muscarine and the analogue shown in Fig. 11.14 are known to bind to the cholinergic receptor. These molecules contain the acetylcholine skeleton,... 

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