Bitolterol

IUPAC nomenclature

(RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl] 4-methylbenzoate.

Classification

Bitolterol is ß₂-adrenergic agonist. [1]

Physiochemical Properties

Mechanism of Action

Relaxation of the smooth muscles surrounding the air flow tubes through agonsim of ß₂ adrenergic receptors. This result in increase in the diameter of the air flow tubes and thus, ease in breathing.

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. Reaction of 2-(tert-butylamino)-1-(3,4-dihydroxyphenyl)ethanone and 4-methylbenzoyl chloride gives compound (1).

ii. Reduction of compound (1) produces Bitolterol.

Therapeutic Uses

Bitolterol is given for the relief of bronchospasm during asthma and Chronic Obstructive Pulmonary Diseases.

Side Effects

Some of the side effects of bitolterol are

• tremors,
• nervousness,
• headache,
• lightheadedness,
• dizziness,
• paresthesia,
• somnolence, etc.

MCQs

Q.1 Match the following with correct SAR of the drug Bitolterol-

 a) i-A, ii-D, iii-B, iv-C

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

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

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

Q.2 correct sequence for the True/False for correct IUPAC names of the drug can be?

• Bitolterol: (RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl] 4-methylbenzoate
• Naphazoline: 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]- 4,5-dihydro-1H-imidazole
• Xylometazoline: 3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol
• Oxymetazoline: 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole

a) TFTF

b) FFFT

c) TFFF

d) FFTT

Q.3 Water solubility of Bitolterol is?

a) 0.00048 mg/ml

b) 48 mg/ml

c) 2 mg/ml

d) 480 mg/ml

Q.4 Agonism of ß₂-adrenergic receptors by Bitolterol leads to?

a) Relaxation of smooth muscles surrounding air flow

b) Increase in diameter of the air flow tubes.

c) Ease in breathing

d) All of the above

Q.5 Which amongst the following is a therapeutic use of drug Bitolterol?

a) Relief in bronchospasm

b) For treatment of ulcers

c) Treatment of insomia

d) None of the above

Q.6 Which of the following drug and their classification are correct?

I. Flutamide: Progestin

II. Etoposide: Epipodophyllotoxin

III. Bitolterol: Nonselective adrenergic agonist

IV. Methamphhetamine: Mixed acting sympathomimetics

a) II, III

b) I, IV

c) I, II, III, IV

d) I

Q.7 Bitolterol can be synthesized by the reaction of-

a) 2-(tert-butylamino)-1-(3,4-dihydroxyphenyl)ethanone and 4-methylbenzoyl chloride; followed by reduction

b) 2-(tert-butylamino)-1-(3,4-dihydroxyphenyl)ethanone and 4-methylbenzoyl chloride; followed by hydrolysis

c) (1-naphthyl)acetonitrile and ethnol; followed by reduction

d) (1-naphthyl)acetonitrile and ethanol; followed by hydrolysis

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ANSWERS

1-b

2-c

3-a

4-d

5-a

6-a

7-a

REFERENCES