Acetylcholine—structure, SAR, and receptor binding

Conclusions clearly, there is a tight fit between acetylcholine and its binding site which leaves little scope for variation. The above findings fit in with a receptor site as shown in Fig. 11.11. 

1 This is due to interactions with other types of receptor, such as the receptors for dopamine or noradrenaline. In the search for a good drug, it is important to gain two types of selectivity—selectivity for one type of receptor over another (e.g. the acetylcholine receptor in preference to a noradrenaline receptor), and selectivity for receptor subtypes (e.g. the muscarinic receptor in preference to a nicotinic receptor). 

2 The search for increasingly selective drugs has led to the discovery that there are subtypes of receptors within subtypes. In other words, not every muscarinic receptor is the same throughout the body. At present, three subtypes of the muscarinic receptor have been discovered and have been labelled Ml, M2, and M3. More may still be discovered. 

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. 

This assumption is invalid since there is not a great energy difference between alternative conformations such as the gauche or staggered conformations (Fig. 11.13). The energy gained from the neurotransmitter-receptor binding interaction would be more than sufficient to compensate for the difference. 

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