Naphazoline

IUPAC nomenclature

2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole.

Classification

Naphazoline is a α₁-adenergic agonist.

Physiochemical Properties

Mechanism of Action

• Naphazoline helps in decreasing congestion at the site of administration through stimulation of the α-adrenergic receptors in the arteriols.
• It also stimulates the release of norepinephrine in the sympathetic nerves, which later binds with α-adrenergic receptors which causes vasoconstriction.
• Naphazoline also acts as mild ß-adrenergic agonist which causes vasodilation after he effect of α-adrenergic is over.
• Due to trigger of negative feedback loop, results in rhinitis medicamentosa after long time administration of Naphazoline when it is stopped.

Structure Activity Relationship

• Primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is essential for the high agonist activity.
• The hydroxyl substituted carbon must be in the R configuration for the maximal direct activity.

R¹ substitution:

• When R¹ is increased in size, activity of alpha receptors decreases and activity of the beta receptors increases
• Activity of both alpha and beta receptors is maximum when R¹ is methyl group.
• Alpha agonist activity decreases when R¹ is larger than methyl, and went negligible when R¹ is isopropyl.
• Large lipophillic groups can afford compounds with alpha blocking activity.
• N-substituent provides selectivity for different receptors.
• Arylalkyl group can provide beta selectivity, increased cell penetration and increased lipophillicity for the longer duration of action.

R² substitution:

• Ethyl group can eliminate the alpha activity of the drug.
• Erythrostero isomers have maximal activity.
• The additional methyl group makes the drug more selective for the alpha₂

R³ substitution on the aromatic ring:

• 3’,4’-dihydroxy substituted benzene ring has poor oral activity.
• 3’, 5’-dihydroxy compounds are orally active.
• At least one of the groups is required which can form hydrogen bonds. And if only one group is present then it is preferred at 4’ position to retain the beta₂
• If phenyl group has no phenolic substituent then it may act directly or indirectly.[2]

Method of synthesis

i. (1-naphthyl)acetonitrile reacts with ethanol to give an iminoester.

ii. The iminoester undergoes cyclization reaction when reacts with ethylinediamine to give naphazoline.

Therapeutic Uses

Naphazoline is used as a degongestant.

Side Effects

Some of the side effects of naphazoline are

• rhinitis medicamentosa
• several hypertensive disorders.

MCQs

Q.1 Correct statements for the Naphazoline drug are?

I. Molecular weight is 210.27gm/mol

II. Water solubility is 31 mg/ml

III. Present as yellow oily liquid at room temperature.

IV. Octanol/water partition coefficient is 3.88

a) I, III

b) I, IV

c) I, II, III

d) IV

Q.2 Match the following of the drugs with their correct IUPAC names.

 a) i-D, ii-A, iii-B, iv-C

b) i-A, ii-C, iii-D, iv-B

c) i-B, ii-C, iii-D, iv-A

d) i-A, ii-D, iii-, iv-B

Q.3 Correct steps for the mechanism of action of the drug Naphazoline?

I. Vasoconstriction

II. Realease of norepinephrine

III. Decrease in the congestion

IV. Stimulation of αadrenergic receptors

a) I – IV – III – II

b) III – II – I – IV

c) I – III – II – IV

d) IV – III – II – I

Q.4 Correct sequence for True/false for the classification of the drug can be?

• Terbutaline: Selective α-adrenergic agonist
• Dopamine: ß-adrenergic agonist
• Phenoxybenzamine: Nonselective adrenergic agonist
• Naphazoline: Mixed acting sympathomimetics

a) FFTF

b) FTFF

c) TFFF

d) FFFF

Q.5 Large lipophillic groups at R₁ substitution can-

a) Afford compounds with α-blocking activity

b) Provides maximal direct activity

c) Increase both α and ß activity

d) None of the above

Q.6 The correct sequence for the steps for synthesis of drug naphazoline from (1-naphthyl)acetonitrile?

I. Reaction with ethanol

II. Reaction with Sulfuric acid

III. Reaction with ethylenediamine

IV. Hydrogenation

a) I – III

b) II – III

c) III – II

d) III – IV

Q.7 Side effect of drug Naphazoline includes?

a) Hair loss

b) Decrease in blood count

c) Rhinitis medicamentosa

d) Liver abnormalities

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ANSWERS

1-b

2-a

3-d

4-d

5-a

6-a

7-c

REFERENCES