SAR of Phenothiazines:
Phenothiazines are a group of drugs, including several antipsychotic medications, that have a three-ring structure in which two benzene rings are joined by a sulfur and a nitrogen atom.
They are part of the larger class of typical, or first-generation, antipsychotics.
The structure-activity relationship (SAR) of phenothiazines is related to the core phenothiazine structure, as well as the various substitutions that can occur on that structure.
·Here are some of the main points:
Three-ring Core Structure:
The core phenothiazine structure is crucial for the antipsychotic activity of these drugs.
The three-ring system with a sulfur atom at the 10-position and a nitrogen atom at the 1-position is common to all phenothiazines.
Side Chain at Nitrogen Atom:
The nature of the side chain at the nitrogen atom (N10 position) significantly affects the activity of the molecule.
Generally, a three-carbon side chain ending in a tertiary amine (like in chlorpromazine) is necessary for antipsychotic activity.
Changes in this side chain can significantly affect the potency and side effect profile of the drug.
Substitutions at 2- and 6- Positions:
Substitutions at the 2- and 6- positions of the phenothiazine ring system can also affect the activity of the drug.
For example, chlorpromazine has a chlorine atom at the 2-position, which may enhance its antipsychotic activity.
Aliphatic Substitution at 3-position:
Aliphatic substitution at the 3-position is essential for the antipsychotic activity.
The introduction of an electron-releasing group at this position increases the potency of these drugs.
Piperazine and Piperidine Ring Substitution:
Phenothiazines can be further classified into aliphatic, piperidine, and piperazine classes based on the type of nitrogen-containing ring in the side chain.
This can affect both the potency of the drug and its side-effect profile. For example, phenothiazines with a piperazine side chain tend to have a higher risk of causing extrapyramidal side effects, while those with a piperidine side chain have a higher sedative effect.
Remember, these are general guidelines, and the activity of a specific drug may not always follow these rules due to the complexity of biological systems and drug-receptor interactions.
