(12) H1 Antagonists

Tell me process of how Histamine and H₁ receptors are released/activated and what happens after.

• Allergen binds a surface antibody called IgE on mast cell /basophil

• histamine is released

• H₁ receptors activate

• leads to symptoms such as runny nose, sneezing, itchy eyes, and itching.

Tell me about H₁ receptor

Gq coupled GPCR

Anaphylaxis treatment

H₁ antihistamines act too slowly to be the main emergency treatment.

Tell me about histamine structure

• Histamine has a side-chain primary amine and an imidazole ring with two nitrogens.

• The π nitrogen is closer to the side chain; the τ nitrogen is farther away.

• NτH has hydrogen on the nitrogen τ. NπH has hydrogen on the nitrogen π.

• Pyrrole like - has N-H

• Pyridine like  - N has NO H

Draw me two types of histamine structures

Tell me about Histamine’s side chain pka

• Histamine’s side chain amine has pKa 9.4 and is positively charged at pH 7.4.

• The basic ring nitrogen has pKa 5.8.

• REFRESHER INFO:

  • Higher pKa → holds onto H⁺ more strongly.

  • higher pKa means more basic. It is more likely to pick up and keep H⁺.

  • Basic nitrogen:
    pH < pKa → protonated → positive (+)
    pH > pKa → unprotonated → neutral

How histamine binds, then activates H₁

• NτH histamine binds H₁: (RECOGNITION)

  • its positive amine attaches to negative Asp107 and forms ion-ion bond

  • while Lys191 and Asn198 help hold it

    • Lys forms ion-dipole bond

    • Asn forms a H-bond

  • H₁ is still off.

• NτH changes to NπH inside H₁ (ACTIVATION)

  • H₁ turns on.

How histamine binds, then activates H₁ - draw it

How H₁ antagonists work

• The antihistamine’s positive amine attaches to Asp107

• Its two aromatic rings fit into two pockets.

• The histamine binding site closes, so histamine cannot turn on H₁.

antagonist structure

Look for	What it helps predict
Anchoring nitrogen	Binding to Asp107 and sedation
X group	Sedation, potency, and motion sickness use
Two aromatic rings	Potency and duration of action

• The general antagonist pharmacophore does not look like histamine

When shown an antagonist structure, how to read?

• find the two rings → follow them to X → follow the chain to the amine.

Anchoring nitrogen

• Most H₁ antagonists have a tertiary amine.

  • Exceptions

    • loratadine = carbamate

    • desloratadine = secondary amine.

• Small amine (straight-chain N,N-dimethyl or pyrrolidine)

  • more likely to enter the brain → more sedation.

• Larger amine ring (piperidine or piperazine)

  • may help keep the drug outside the brain → less sedation.

  • A large ring alone is not enough to decide.

• First generation: some sedation. Second generation: marketed as nonsedating.

Spacer Group

x group

X group	Class	Remember
CH–O	Aminoalkyl ether	Among the most sedating; diphenhydramine is an example
CH or C=C	Alkylamine	Among the most potent first generation agents
N	Ethylenediamine	Two nitrogens; often used for motion sickness/antiemetic effects

REMEMBER, THEY ALL ARE FIRST GENERATION ANTIHISTAMINE, SO ALL SEDATING!! THIS ABOUT WHO IS MORE OF WHAT!!!

Spacer Group

2 Aromatic rings - structure

Spacer Group

Tell me about the 2 Aromatic rings and how it binds to the H1?

• Trp158 = larger van der Waals pocket. The cis ring binds here.

• Phe432 = smaller hydrophobic pocket. The trans ring binds here.

• A bulky para substituent such as Cl fits the larger Trp pocket, so only one ring can carry it in this arrangement.