Diphenhydramine hydrochloride

Structure

• Chemical formula of Diphenhydramine hydrochloride – C17H21NO.HCl

Mode of action

• Diphenhydramine reverses the effects of histamine on capillaries by acting as an inverse agonist at the H1 receptor, which reduces allergic reaction symptoms.

• It also acts on CNS and cause sedation and drowsiness.

• It has some antimuscarinic properties as well.

• By acting as an intracellular sodium channel blocker, it also exhibits local anaesthetic characteristics.

SAR

• Diphenhydramine is a first-generation antihistamine belonging to the ethanolamine class of antihistamines, which also includes drugs like dimenhydrinate and doxylamine.

• Here's a general Structure-Activity Relationship (SAR) for this class of drugs:

1.  Basic Nitrogen: 

• Essential for the activity of the compound. The nitrogen atom, being part of a secondary or tertiary amine, allows the drug to have the correct balance of lipophilicity and hydrophilicity to cross the blood-brain barrier.

2. Ethanolamine Side Chain: 

• The ethanolamine side chain is responsible for the sedative effects of the drug. Modifications to this side chain may lead to changes in the drug's sedative properties.

3.  Two aromatic rings: 

• The two aromatic rings provide significant lipophilicity, aiding in crossing the blood-brain barrier.

4.  Substitution on Aromatic Rings: 

• Substitution on the aromatic rings (like the presence of two methyl groups on one of the aromatic rings in diphenhydramine) can influence the potency and selectivity of the compound.
  

Structure-Activity Relationship (SAR) of Diphenhydramine Hydrochloride

• Diphenhydramine hydrochloride is a first-generation antihistamine with sedative and anticholinergic properties.

• The structure-activity relationship (SAR) of diphenhydramine can be understood by analyzing the key structural features that contribute to its pharmacological activity:

1.   Ethanolamine Core:

• Diphenhydramine features an ethanolamine core, a common structural motif in many first-generation antihistamines.

• This feature is crucial for the antihistaminic activity.

2.  Diphenylmethyl Group:

• The presence of a diphenylmethyl group (two benzene rings attached to a methyl group) is essential for the histamine H1 receptor antagonism.

• This group contributes to the molecule's lipophilicity, aiding in its ability to cross the blood-brain barrier, resulting in sedative effects.

3.   Dimethylamino Group:

• The dimethylamino group is a key structural element for the anticholinergic activity of diphenhydramine.

• This tertiary amine is responsible for the molecule's binding affinity to muscarinic receptors, contributing to its side effects like dry mouth and urinary retention.

4.  Hydrochloride Salt Form:

• The hydrochloride (HCl) salt form increases the solubility of diphenhydramine in water, making it more suitable for oral or parenteral administration.

5.   Flexibility:

• The flexible ethylene bridge between the aromatic ring and the amine group allows the molecule to conform to different shapes, adapting to various receptors, which is a characteristic feature of many antihistamines.

Synthesis of Diphenhydramine Hydrochloride

• The chemical synthesis of diphenhydramine hydrochloride can be outlined as follows:

1.   Start with Benzhydrol:

• The synthesis begins with benzhydrol (diphenylmethanol).

2.   Chlorination:

• Benzhydrol is treated with thionyl chloride (SOCl₂) or hydrochloric acid to form diphenylmethyl chloride (chlorodiphenylmethane).

C13​H12​OH + SOCl2 ​→ C13​H11​Cl + SO2 ​+ HCl

3.   Formation of Diphenhydramine:

• The resulting chloride compound is then reacted with dimethylamine, forming diphenhydramine.

C13​H11​Cl + (CH3​)2​NH → C17​H21​N + HCl

4.   Formation of the Hydrochloride Salt:

• Finally, the free base form of diphenhydramine is treated with hydrochloric acid to form diphenhydramine hydrochloride.

C17​H21​N + HCl → C17​H21​N⋅HCl

• This synthesis route is a common method in the pharmaceutical industry for producing diphenhydramine hydrochloride.

• The process involves standard techniques in organic synthesis, such as chlorination and amine alkylation.

Uses

• Diphenhydramine is used to treat hay fever, allergies, or the common cold-related runny nose, sneezing, and red, itchy, and watery eyes.

• Diphenhydramine is also used to treat cough caused on by mild irritation of the throat or lungs.

• It easily passes the blood-brain barrier, induces drowsiness, and is used to relax and sleep.

• Also used in the treatment of Parkinson’s disease because it has antimuscarinic activity.