SAR of LAs 



Aryl Group (lipophilic portion) –

*       The aryl group is the most important functional group for the lipophilicity of LA. Aryl group helps the LA to cross the cell membrane.

*       Substitution of aryl group alters the potency.

-        Substitution of EDG (methoxy, Amino) enhances potency  

-        Substitution of EWG (carbonyl, halogen) decreases potency.

*       Substitution that enhances the formation of Zwitterion increases the potency.

Bridge/intermediate linker – (Ester/amide/thioester/thioamide)

*       The intermediate bridge can be C, O, N or S.

*       Isosteres of these atoms can alter the potency. For example

Esters are less potent than Amides.

*       These modifications can also alter the Duration of Action (DOA)

For example, Amides are more resistant to metabolic hydrolysis than Esters.

*       Increasing chain length will increase potency but, will also increase TOXICITY.

 

Hydrophilic Portion (Aminoalkyl group) –

*       Aminoalkyl group is not necessary for LA action but is important for the formation of water-soluble salts.

*       Tertiary amines are more useful,

*       Secondary amines have longer duration of Action but more irritating

*       Primary amines are inactive.


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