SAR of barbiturates:
The structure-activity relationship (SAR) in barbiturates refers to the relationship between the chemical or 3D structure of the drug molecule and its biological activity.
Various modifications in the structure of barbiturates can significantly affect their pharmacological activity.
The basic structure of barbiturates is derived from barbituric acid, which contains a six-membered pyrimidine ring with two carbonyl groups at the 2 and 4 positions and two nitrogen atoms at positions 1 and 3.
Here are some general rules regarding the structure-activity relationship of barbiturates:
1.Alkyl Substitutions at C5:
Alkyl substitutions at C5 position influence the lipid solubility and thus, the onset and duration of action of the barbiturate.
For example, increasing the chain length of the alkyl groups generally increases lipid solubility, leading to a quicker onset and shorter duration of action (e.g., pentobarbital and secobarbital).
2.Substitutions at N1 and N3:
Generally, substitutions at N1 and N3 do not dramatically influence the hypnotic activity, but they do affect the stability of the molecule.
For instance, thiobarbiturates, where the oxygen at the 2nd position is replaced by a sulfur atom, are more lipid-soluble and have a faster onset of action.
3.Branching of Alkyl Groups:
Bulky substitutions or branching of the alkyl groups at C5 position may lead to a reduction in the duration of action and an increase in the induction time.
4.Unsaturation and Aromatic Rings:
Introducing unsaturation or aromatic rings at C5 position can increase the potency of the molecule. Phenobarbital is an example of this.
5.Stereochemistry:
The configuration of the two carbon atoms at C5 also influences the activity of the drug.
Barbiturates are usually more active in the racemic form than as individual enantiomers.
