The size of the nitrogen substituent is critical. After this, the activity drops off, since the analogues are too lipid soluble. Branching also increases potency. Usually the N-substituent is methyl, ethyl or propyl, or is included in a ring structure such as a piperidine. Addition of polar substituents on the N-substituent, such as a hydroxyl, will greatly diminish activity.
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.