Examination of the active compounds discussed in the following sections reveals that at least one cyclic substituent
(phenyl, thienyl, or other) is a common feature in almost all anticholinergic molecules. Aromatic substitution is often used in connection with the acidic moiety of the ester function. Virtually all acids used, however, are of the aryl-substituted acetic acid variety. Use of aromatic acids leads to low activity of these compounds as anticholinergics but potential activity as local anesthetics.
In connection with the apparent need for a cyclic group, Ariens68 points out that the "mimetic" molecules, richly endowed with polar groups, undoubtedly require a complementary polar receptor area for effective binding. As a consequence, it is implied that a relatively nonpolar area surrounds such sites. Thus, increasing the binding of the molecule in this peripheral area by introducing flat, nonpolar groups (e.g., aromatic rings) should achieve compounds with excellent affinity but without intrinsic activity. This postulate is consistent with most antimuscarinic drugs, whether they possess an ester group or not.
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