Terbutaline

IUPAC nomenclature

(RS)-5-[2-(tert-Butylamino)-1-hydroxyethyl]benzene-1,3-diol.

Classification

Terbutaline is ß₂-adrenergic agonist. [1]

Physiochemical Properties

Mechanism of Action

i. Adenyl cyclase enzyme is stimulated through the ß-adrenergic receptors.

ii. The conversion of ATP to cyclic AMP also increases due to this.

iii. Due to raise in level of CAMP, relaxation of bronchial smooth muscles and inhibition of release mediators of immediate hypersensitivity from mast cells takes place.

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. Bromination of 3,5-dibenzyloxyacetophenone gives 3,5-dibenzyloxybromoacetophenone.

ii. It is then reacted with N-benzyl-N-tert-butylamine to give a ketone intermediate.

iii. Intermediate undergoes reduction to give terbutaline.

Therapeutic Uses

The drug is used:

• As a bronchodilator
• Treatment of asthma
• As a tocolytic

 Side Effects

Common side effects of terbutaline are

• tachycardia,
• hypotension,
• hypokalemia,
• hyperglycemia,
• headache,
• tremors,
• anxiety and nervousness.

Less common side effect of this drug is pulmonary edema.

MCQs

Q.1 “(RS)-5-[2-(tert-Butylamino)-1-hydroxyethyl]benzene-1,3-diol” is the IUPAC nomenclature of which drug?

a) Terbutaline

b) Doxazocin

c) Methoxamine

d) Phenoxybenzamine

Q.2 Number of chiral carbons in the structure of Terbutaline is?

a) 0

b) 1

c) 2

d) 3

Q.3 Match the following with correct classifications of the drugs.

 a) i-D, ii-C, iii-B, iv-A

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

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

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

Q.4 Correct steps for the mechanism of action of the drug…..

I. Stimulation of Adenyl cyclase enzyme.

II. Relaxation in bronchial smooth muscles.

III. Conversion of ATP into CAMP increases.

a) I – II – III

b) II – I – III

c) I – III – II

d) III – II – I

Q.5   Correct sequence for True and False for the given statements related with the SAR of drug Xylometazoline.

• When R¹ is increased in size, activity of alpha receptors decreases and activity of the beta receptors increases
• 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 activity
• Activity of both alpha and beta receptors is maximum when R¹ is methyl group.
• Primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is essential for the high agonist activity.

a) TTFT

b) TTTF

c) TFTF

d) TTTT

Q.6 Type of ring present in the structure of Terbutaline?

a) Benzene

b) Imidazoline

c) Both a) and b)

d) No rings are present

 Q.7 The drug that can be given for relief in bronchospasm?

a) Terbutaline

b) Vincristine

c) Fludarabine

d) Vinblastine

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ANSWERS

1-a

2-b

3-a

4-c

5-d

6-a

7-a

REFERENCES