| Candidate ID: | R0319 |
| Source ID: | DB01075 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
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| Compound Name: |
Diphenhydramine
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| Synonyms: |
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| Molecular Formula: |
C17H21NO
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| SMILES: |
CN(C)CCOC(C1=CC=CC=C1)C1=CC=CC=C1
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| Structure: |
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| DrugBank Description: |
Diphenhydramine - perhaps known most commonly as its brand name formulation Benadryl - is a first-generation H1 receptor antihistamine that is used extensively for the treatment of seasonal allergies, insect bites and stings, and rashes [L5263, L5266, L5269, F3379]. However, it also has antiemetic, antitussive, hypnotic, and antiparkinson properties [L5269, F3352]. As histamine receptors exist both peripherally and in the central nervous system, diphenhydramine has been shown to cause sedation due to its competitive antagonism of histamine H1 receptors within the central nervous system [L5263, L5266, L5269, F3379, A174541]. While its use in allergy therapy can sometimes fall out of favor due to its sedative effect, diphenhydramine has been repurposed for use within many non-prescription over-the-counter sleep aids and cough-and-cold medications that have been marketed for "night time" use [L5263, L5281, L5287].
Diphenhydramine is also used in combination with [DB14132] as the anti-nausea drug [DB00985] where it is utilized primarily for its antagonism of H1 histamine receptors within the vestibular system [A1540].
Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behaviour including dopamine, norepinephrine, serotonin, acetylcholine, and opioid [A1539]. As a result, diphenhydramine is being investigated for its anxiolytic and anti-depressant properties.
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| CAS Number: |
58-73-1
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| Molecular Weight: |
255.3547
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| DrugBank Indication: |
Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea [L5263, L5266, L5269, F3379, A174541].
Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for:
i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated [F3352];
ii) the active treatment of motion sickness [F3352]; and
iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents [F3352].
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| DrugBank Pharmacology: |
Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties [L5281]. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone [L5281]. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere [L5281]. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone [L5281]. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain [L5281].
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| DrugBank MoA: |
Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors [L5263, L5266, L5269, F3379, A174541]. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons [L5263, L5266, L5269, F3379, A174541]. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response [L5263, L5266, L5269, F3379, A174541].
Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms [L5263, L5266, L5269, F3379, A174541]. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center [L5263, L5266, L5269, F3379, A174541].
Furthermore, H1 receptors are similar to muscarinic receptors [L5263, L5266, L5269, F3379, A174541]. Consequently, diphenhydramine also acts as an antimuscarinic [L5263, L5266, L5269, F3379, A174541]. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication [L5263, L5266, L5269, F3379, A174541].
Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties [L5263].
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| Targets: |
Histamine H1 receptor; Muscarinic acetylcholine receptor M2
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| Inclusion Criteria: |
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