Some analogues have no amino group at all, such as benzocaine. They are active, but have poor water solubility. This effect is not seen in the lidocaine series. Increasing the chain length will increase potency but will also increase toxicity. There is some variability in the functional group seen in the intermediate chain, as shown below.
Esters are the most common functional group.
The carbonyl must be in conjugation with the aromatic ring for activity. Reverse esters are inactive, and compounds with a methylene inserted between the carbonyl and the aromatic ring have poor activity and anticholinergic side effects. Thioesters have increased activity, but are more rapidly hydrolyzed than esters. Amides can also be active, but their activity depends on the overall structure. Conversion of procain to procainamide destroys anesthetic activity and reduces lipid solubility, but does increase the stability of the analogue.