(13) H1 Antagonists

Where the aromatic rings bind?

Ring	Pocket	Why an aromatic ring is needed
Cis (same side as the amine)	TRP/W158	Big-Makes van der Waals interactions.
Trans (opposite side)	PHE432	Small-Fits the pocket’s flat shape.

Where the aromatic rings bind? - draw it

What role does the substituent on the aromatic ring play here?”

• A substituent such as para-Cl makes a ring bulkier.

• That ring must enter the larger TRP pocket; the smaller PHE pocket cannot fit it.

What are effects of adding para-Cl to the drug’s structure?

• Longer action: It blocks a para position where the drug could be broken down.

  • Cl → less breakdown + better access to the receptor.

• Greater potency: It is lipophilic, helping more drug reach H₁ receptors in the cell membrane.

What antihistamines are non-sedative?

• Zwitterions

  • Fexofenadine (Allegra)

  • Cetirizine (Zyrtec)

Zwitterions

topics

• structure

• sedation

• how they bind to H₁

What makes Fexofenadine and Cetirizine a Zwitterion? (aka structure)

• each has a positive amine and a negative carboxylate.

• Look for the carboxylic acid tail to recognize them.

What makes Fexofenadine and Cetirizine a Zwitterion? - draw it

Tell me about fexofenadine and cetirizine sedation?

• fexofenadine and cetirizine cause little sedation. reason:

  • They act mainly outside the CNS because they have:

    • Strong plasma protein binding

    • Little active transport into the CNS

    • P-gp efflux, which pumps them out if they enter

Tell me about fexofenadine and cetirizine binding to H₁

They bind to H₁ strongly:

• Amine binds ASP + aromatic rings enter their pockets + carboxylate binds LYS

  • That second ion–ion bond with LYS makes binding very strong.

  • The professor called it pseudoirreversible: the drug does not come off the receptor easily.

fexofenadine and cetirizine binding to H₁ - draw it

Antihistamine drugs overview

• Non-Sedative/Zwitterionic

  • Fexofenadine (Allegra)

  • Cetirizine (Zyrtec)

• Aminoalkyl Ethers (Structural Class)

  • Diphenhydramine (Benadryl)

  • Carbinoxamine

    • Analogs

      • Doxylamine and clemastine

• Alkylamines (Structural Class)

  • Chlorpheniramine

  • Brompheniramine

  • Fexofenadine - zwitterionic

  • Non-tertiary amine

    • Loratadine (Claritin)

    • Desloratadine (Clarinex)

  • Azelastine (NEXT FC)

  • Triprolidine (NEXT FC)

Dippy’s CAR drove DOXY and CLEM to bed

CHLOR and BROM follow FEXO. LORA and DES take AZ TRIP

Aminoalkyl ethers

Main Point

• Among the most sedating;

  • Small groups on the amine also favor sedation and CNS entry.

Aminoalkyl ethers drugs

Drugs

Drug	Main points
Diphenhydramine (Benadryl)	Highly sedating: ether spacer + small N-methyl groups. (Used in sleep aids) No para substituent → relatively quicker breakdown. No chiral center. similar to antimuscarinics
Carbinoxamine	A sedating ether. Its para-Cl increases potency and duration compared with diphenhydramine. Chiral center - S form is active.
Carbinoxamine Analogs: Doxylamine and clemastine	Same as Carbinoxamine (Doxylamine is used as a sleep aid)

Diphenhydramine (Benadryl) - draw

Carbinoxamine - draw

Doxylamine - draw

Clemastine - draw

Alkylamines

Main Points

• Among the most potent first generation agents

• less sedation.

Alkylamines

Drugs

Drug	Main points
Chlorpheniramine	More potent and less sedating than carbinoxamine, but still sedating. Its para-Cl has the same two effects S form is active, but the product contains both R and S.
Brompheniramine	Chlorpheniramine with Br instead of Cl.
Fexofenadine	Structurally an alkylamine, but recognize it mainly by its zwitterionic carboxylic acid tail. It has a chiral center, but R and S bind equally well in the professor’s explanation. It acts mainly in the periphery. Most drug is excreted essentially unchanged.A

Additional Drugs

• Non-tertiary amine

  • Loratadine (Claritin)

  • Desloratadine (Clarinex)

• Azelastine (NEXT FC)

• Triprolidine (NEXT FC)

Chlorpheniramine - draw

Brompheniramine - draw

• Chlorpheniramine with Br instead of Cl.

Fexofenadine - draw

Non-tertiary amine

Main Point

• Both drugs have two linked aromatic rings

• Their chlorinated ring enters TRP.

• Loratadine → desloratadine

Non-tertiary amine

Drugs

Drug	Nitrogen	Result
Loratadine (Claritin)	Carbamate does not readily become positive	Acts mainly as a prodrug. Makes a weak ASP contact.
Desloratadine (Clarinex)	Secondary amine can become positive	Binds ASP as the active drug. About 4 times more potent than loratadine on the slide.

Loratadine (Claritin) - draw

Desloratadine (Clarinex) - draw

Describe Conversion:

Loratadine → desloratadine

Loratadine →

(CYP 3A4 metabolism)→

unstable hemiacetal →

unstable carbamic acid →

(CO₂ leaves) →

desloratadine

Draw Conversion:

Loratadine → desloratadine