Structure Activity Relationships of some Muscarinic Agonists: a Reply to Shefter and Triggle

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IN essence, the criticism by Shefter and Triggle1 of my model2 for the interaction of acetylcholine, (CH3)3N+-CH2CH2OCOCH3, with muscarinic receptors is that it does not explain the muscarinic potency of some analogues of acetylcholine. I believe that my model does quite simply account for the activity of these compounds. As background information for my model, I made the general statement that muscarinic agonists are observed to have the N+–C–C–O torsion angle between the positive synclinal and positive anticlinal2 (Fig. 1a). Shefter and Triggle do not quote any potent agonists for which this observation is untrue and I briefly show how it can be used to explain the muscarinic activity of the compounds they mention.

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CHOTHIA, C. Structure Activity Relationships of some Muscarinic Agonists: a Reply to Shefter and Triggle. Nature 227, 1355–1356 (1970) doi:10.1038/2271355a0

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