Histamine is an organic compound involved in many physiological roles and is the endogenous ligand of histamine receptors. Histamine is involved in roles such as local immune response and neurotransmission, as well as stimulating gastric acid secretion. Here, we focus on the medicinal chemistry of antihistamines used for treating allergic response.

Histamine Receptors

There are four known histamine receptors (HR) that are G-protein coupled receptors (GPCR), H1 to H4. The molecule histamine is the endogenous ligand of these.

Chemistry of Histamine

Histamine consists of an imidazole ring and an aliphatic amino group (an ethylamine side chain). In an aqueous environment, the imidazole ring exists in the tautomeric forms::

The naming system is based on which of the two imidazole nitrogens is protonated

tele tautomer:

  • Denoted by the Greek letter lowercase tau (τ)
  • NH furthest from the ethylamine side chain
  • Also referred to as Nτ-H-histamine

pros tautomer:

  • Denoted by the Greek letter lowercase pi (π)
  • NH closest to the ethylamine side chain
  • Also referred to as Nπ-H-histamine

Given the pKa (~9.4) of the aliphatic amino group, the protonated form of this amino group is predominant at physiological pH (7.4). The protonated forms are said to be monocationic.

Biosynthesis of Histamine

Histamine is bioderived from the naturally-occurring L-amino acid, histidine via a decarboxylation reaction, catalysed by specific decarboxylase enzymes:

  • Pyridoxal phosphate dependent enzyme histidine decarboxylase or
  • L-aromatic amino acid decarboxylase

Binding of Histamine to H1 Receptors

In the case of H1 receptors, histamine tautomerization is important:

  • Tele tautomer: critical for initial receptor binding
  • Pros tautomer: critical for receptor activation

The key amino acids for binding histamine in the H1 receptor are

  • Asp107
  • Lys191
  • Asn198

Histamine binding and activation occurs in three stages:

1) Initial receptor binding (tele tautomer)

2) Proton transfer

3) Receptor activation (pros tautomer)

1) Initial Receptor Binding

As mentioned earlier, the monocationic form is predominant at physiological pH. The H1 receptor recognises the tele tautomer during initial receptor binding and the key intermolecular interactions are summarised below:

2) Proton Transfer

Following initial recognition, proton transfer occurs, favoring pros tautomer formation.

3) Receptor Activation
The key intermolecular interactions between the pros tautomer and the H1 receptor binding site are summarized below. Receptor activation occurs at this stage.

H1 Antihistamines:

Going forward in our analysis of the medicinal chemistry of antihistamines, when we talk about an ‘antihistamine’, we refer to H1 antihistamines.

Medications that block the action of histamines at the H1 receptor are called antihistamines. H1 antihistamines for the treatment of histamine-mediated allergic conditions function by:

  • Inverse agonism (majority of antihistamines)
    • The drug molecule binds to an inactive form of H1, shifting the conformational form to the inactive one.
  • Classic antagonism

The typical structure of an antihistamine is:

  • Typically aromatic moieties covalently bonded to X. The X moiety dictates the class of antihistamine:
Class Example
Polycyclics (tricyclics and tetracyclics)
  • Chirality at X can dictate antihistamine potency. S-enantiomers are usually eutomers.
  • Aromatic substituents interact with the receptor via interactions such as van der Waals interactions.
    • The aromatic substituents also confer greater lipophilicity
  • Spacer units are generally unsubstituted and comprise of 2 to 3 carbons. Can be a ring (e.g. piperazine class of antihistamines)
  • The amino group (pKa~8.5 – 9.5) is generally cationic at physiological pH (7.4). This cationic group is essential as it facilitates anchorage to the H1 binding site via ion-ion interactions with Asp107, in a similar fashion as with histamine.
    • Tertiary amines typically have the greatest antihistaminic activity.
    • This amino group is usually substituted with small alkyl groups (e.g. methyl)
    • In the case of cetirizine and fexofenadine, both these second-generation antihistamines have a long and flexible chain.

Antihistamines are subdivided as follows:

  • First Generation Antihistamines:
    • Older
    • Greater CNS activity
    • Examples: Chlorphenamine and Promethazine
  • Second Generation Antihistamines:
    • More peripherally selective
    • Most are zwitterionic at physiological pH, thus conferring increased polarity and consequently reducing ability to cross the blood-brain barrier (BBB).
    • Have little sedative effect
    • Examples: Cetirizine and Loratadine

There is approximately 40% homology between the muscarinic M1 and M2 receptors and the H1 receptor. The adverse effects associated with antihistamines, particularly first generation antihistamines, such as blurry vision and xerostomia (dry mouth), are partly due to binding to muscarinic receptors. First generation antihistamines also tend to be lipophilic enough to be able to cross the BBB, allowing for the interaction with central H1 receptors and ultimately leading to sedation.

As mentioned earlier, both cetirizine and fexofenadine have long, flexible aliphatic chains terminating with a carboxylic acidat the amino group that interacts with Asp107.

  • A folded internal salt forms between the aforementioned amino group and the terminal carboxylic acid.
  • Since they’re internal salts, they have enhanced polar character and reduced ability to traverse the BBB.
  • The folded form is prevalent in the bloodstream.
  • The folded form has lower affinity for CNS transport proteins, thus also contributing to higher concentrations in the periphery.

  • In the case of fexofenadine, upon binding to peripheral H1 receptors, the extended conformation of the antihistamine binds to the receptor via an extra ion-ion interaction, thus enhancing binding to the receptor.

Loratadine Metabolism

Orally-administered loratadine is well-absorbed in the gastrointestinal tract and undergoes rapid first-pass hepatic metabolism calaysed by cytochrome p450 enzymes CYP3A4, CYP2D6, CYP1A1 and CYP2C19. A major metabolite of loratadine, desloratadine, possesses more potent pharmacological activity in comparison to loratadine. The key difference between loratadine and desloratadine is the absence of an ethyl carbamate-type moiety in desloratadine. Since desloratadine does not readily enter the CNS, it has minimal sedative effects.

Further Reading

1) Panula P, Chazot PL, Cowart M, et al. (2015). “International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors”. Pharmacol. Rev. 67 (3): 601–55.

2) Lemke, TL.,Zito, SW., Roche, VF., et al, (2017). “Essentials of Foye’s Principles of Medicinal Chemistry of Antihistamines”. Wolters Kluwer, Lippincott Williams & Wilkins, Baltimore, MD, USA.

3) Shargel, L., Mutnick, AH., Souney, PF., Swanson, LN., Eds. (2013). Comprehensive Pharmacy Review for NAPLEX 8<th Edition; Lippincott Williams & Wilkins: Baltimore, MD, USA.