1. Aromatic Group (Lipophilic End):
This part of the molecule is usually a benzene ring. It's responsible for the lipophilic properties of the molecule, allowing it to interact with the lipid-rich environment of nerve cell membranes.
The potency of the anesthetic is often proportional to its lipid solubility, as this determines the drug’s ability to penetrate nerve membranes.
2. Intermediate Chain (Linker):
The intermediate chain links the aromatic group to the ionizable group. It can be either an ester or an amide linkage.
Ester-linked Local Anesthetics:
These are generally metabolized by plasma cholinesterases and are more likely to cause allergic reactions.
Amide-linked Local Anesthetics:
These are metabolized in the liver and are less likely to cause allergic reactions. They typically have a longer duration of action than ester-linked anesthetics.
3. Ionizable Group (Hydrophilic End):
This is usually a tertiary amine. It's responsible for the hydrophilic properties of the molecule.
The degree of ionization of this part is important for the onset of action. Local anesthetics are weak bases and are more effective in their non-ionized form, as this form more readily penetrates nerve membranes. However, once inside the nerve cell, the ionized form is essential for binding to and blocking sodium channels, which is the primary mechanism of action.
Additional SAR Aspects:
Stereochemistry: The stereochemistry of the molecule can influence its anesthetic activity and toxicity. For example, bupivacaine has a significant difference in toxicity between its enantiomers.
Length of the Intermediate Chain: The length and composition of the intermediate chain can affect the onset and duration of action. Longer chains generally result in a longer duration of action.
Substituents on the Aromatic Ring: Substituents on the aromatic ring can affect potency and toxicity. For instance, the addition of lipophilic groups can increase potency, while hydrophilic groups might reduce it.
Here is the mind map illustrating the Structure-Activity Relationship (SAR) of Local Anesthetics: