SAR of Local Anaesthetics
SAR of Benzoic Acid Derivatives
Mostly, the benzoic acid derivatives are tertiary amines found as HCl salts
having pKa in the range of 7.5 -9.0. Any structural modificati on in these local
anaesthetics that may alter the pKa will have a pronounced effect to reach
hypothetical receptor or the binding sites.
1) Lipophilic Portion
i) A local anaesthetic of this class that is clinically useful is highly
lipophilic and has an aryl radical directly attached to the carbonyl group.
This plays an import ant role in the binding of local anaesthetics to the
channel receptor protein.
ii) Placing the aryl group with substituents that increases the electron
density of carbonyl oxygen enhances the activity of local anaesthetics.
iii) Structural modification change s the physical and chemical properties of
local anaesthetics . Placement of electron withdrawing substituents at ortho or para or both the positions increase s the activity of local anaesthetics.
iv) Amino (procaine, butacaine) , alkyl amino (tetracaine) , and alkoxyl
(cyclomethycaine) groups contribute to electron density in the aromatic
ring by resonance and inductive effects. This increases the activity of
v) Any substitution that enhances the formation of Zwitter ion will be more
potent. Hence substitution at m-position decreases the activity of local
vi) The potency of tetracaine is 40 -50 times more than that of procaine.
Although the butyl group present in it increases lipid solubility, the
potentiation is partially due to ele ctron releasing property of the n -butyl
group via inductive effect, which increases the formation of Zwitter ion.
vii) Electron withdrawing group (Cl –
) if present ortho to carbonyl pulls the
electron density away from carbonyl group, and makes it more
susceptible to nucleophilic attack by the esterase.
2) Intermediate Portion
i) In procaine series, the anaesthetic potency decreases in the following
order: sulphur > oxygen > carbon > nitrogen.
ii) Modifications affect the duration of action and toxicity. Amides (X = N)
are more resistant to metabolic hydrolysis than esters (X = O). Thioesters
(X = S) may cause dermatitis.
iii) Substitution of small alkyl groups (branching) around ester group
(hexylcaine/meprylcaine) or amide function delays hydrolysis and
increases the duration of action.
3) Hydrophilic Portion
i) The amino alkyl group is not necessary for local anaesthetic activity, but
for forming water-soluble salts such as HCl salts.
ii) Tertiary amines are more useful. Secondary amines have a longer
duration of action, but are more ir ritating. Primary amines are inactive and cause irritation.
iii) Placement of tertiary amino group (diethyl amino, piperidine, or pyrrolidino) forms a product with same degree of activity.
iv) Placement of a more hydrophilic morpholino group reduces the potency.
v) The local anaesthetic drug should have increased lipid solubility and
lower pKa values to increase the onset of action and decrease toxicity.