Structure
Promethazine hydrochloride Molecular Formula - C17H20N2S.ClH
Mode of action
Alpha adrenergic, muscarinic, NMDA, post-synaptic mesolimbic dopamine, and histamine H1 receptors are all antagonists of promethazine.
Structure-Activity Relationship (SAR) of Promethazine Hydrochloride
Promethazine hydrochloride is a first-generation antihistamine with strong sedative and anticholinergic properties. It is also used as an antiemetic.
The SAR of promethazine can be described as follows:
1. Phenothiazine Core:
The core structure of promethazine is a tricyclic phenothiazine.
This ring system is crucial for its antihistaminic activity.
The two benzene rings connected by a sulfur and nitrogen bridge (phenothiazine) contribute significantly to its binding affinity to the H1 receptor.
2. Alkylamine Side Chain:
The ethylamine side chain at the nitrogen atom of the phenothiazine ring is a key structural feature.
The length and flexibility of this side chain are essential for the antihistaminic and anticholinergic activities.
3. Dimethylamino Group:
The tertiary dimethylamino group at the end of the side chain is responsible for the anticholinergic effects.
This group enhances the drug's lipophilicity, allowing it to cross the blood-brain barrier and contribute to its sedative properties.
4. Substituents on the Phenothiazine Ring:
The presence of a chlorine atom at position 2 of one of the benzene rings increases the lipophilicity of the molecule, which is important for its central nervous system effects.
5. Hydrochloride Salt Form:
The hydrochloride salt form of promethazine enhances its water solubility, facilitating its administration and absorption.
Synthesis of Promethazine Hydrochloride
The synthesis of promethazine hydrochloride typically involves several steps, starting from phenothiazine as a core structure.
The synthesis can be described in simplified form as:
Substitution Reaction:
The synthesis begins with a substitution reaction on phenothiazine.
Chlorpromazine is often used as a starting material, which already contains the chlorine substituent on the phenothiazine ring.
Formation of the Side Chain:
The side chain is introduced through an alkylation reaction.
This involves the reaction of the phenothiazine derivative with a suitable alkyl halide (like 3-dimethylamino-1-propyl chloride) to form the desired alkylamine side chain.
Conversion to Hydrochloride Salt:
The free base form of promethazine is then converted to its hydrochloride salt form.
This is typically achieved by treating the free base with hydrochloric acid.
Promethazine (free base) + HCl → Promethazine hydrochloride
Uses
Promethazine is used in combination with other drugs to treat anaphylaxis (sudden, severe allergic responses) and cold-related symptoms as runny nose, coughing, and sneezing.