Clonidine

IUPAC nomenclature

N-(2,6-Dichlorophenyl)-4,5–1H-imidazol-2-amine.

Classification

Clonidine is an α₂-Adrenergic agonist. [1]

Physiochemical Properties

Mechanism of Action

• The α₂-adrenoceptor is coupled with the G-proteins G₀ and G₁. G₁ inhibits the adenyl cyclase and activates opening of a potassium channel that causes hyperpolarization.
• Clonidine also reduces the binding affinity of the G-protein for the GDP, by binding with the α₂-adrenoceptors.
• Hypnotic effects of the clonidine are due to stimulation of α₂-adrenoceptos in the locus cioeruleus.
• Clonidine is also helpful in reduction of transmission of the pain signals at te spine.
• In the medulla, clonidine can affect the regulation of the blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla.

 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. 2,3-dichloroanilline reacts with ammonium thiocyanate to give thiourea.

ii. Thiourea is treated with methy iodide to give S-methylthiouronium salt.

iii. Latter compound is treated with ethylenediamine to give clonidine.

Therapeutic Uses

The drug used for the treatment of:

• High blood pressure
• Attention deficit hyperactivity disorder
• Menopausal flushing
• Diarrhea
• Some pain conditions

 Side Effects

Common side effects of clonidine are dizziness, hypotension, skin reactions, fatigue, headaches, dry mouth, erectile dysfunction, pain below ear, weight changes rashes, malaise, nausea and vomiting.

Some of the less frequent side effects are urticaria, pruritus, Raynaud’s phenomenon, sinus bradycardia, paresthasia, nightmare, hallucination, delusions, gynaecomastia and nasal dryness.

MCQs

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

 a) i-D, ii-A, iii-B, iv-C

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

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

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

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

• “ N-(2,6-Dichlorophenyl)-4,5–1H-imidazol-2-amine” is for Clonidine
• “4-(2-Aminoethyl)benzene-1,2-diol” is for Dopamine
• “(RS)-4-(2-{[4-(4-hydroxyphenyl)butan-2-yl]amino}ethyl)benzene-1,2-diol” is for Dobutamine
• “ N-(2,6-Dichlorophenyl)amine” is for Methyldopa

a) TTFT

b) TTTF

c) FFTF

d) TFTF

Q.3 Number of chiral centers in the structure of clonidine is?

a) 0

b) 1

c) 2

d) 3

Q.4 Clonidine produces its action through binding with?

a) α₁-adrenergic receptors

b) α_2-adrenergic receptors

c) ß₁– adrenergic receptors

d) ß₂ – adrenergic receptors

Q.5 Which amongst the following is not a therapeutic use of drug Clonidine?

a) Treatment of low blood pressure

b) treatment of Attention Deficit disorder

c) Treatment of menopausal flushing

d) None of the above

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

I. Vincristine: Vinca alkaloids

II. Flutamide :Nitrosaureas

III. Clonidine: Selective α₂-adrenergic agonist

IV. Epinephrine: ß-adrenergic antagonist

a) II, IV

b) I, III

c) I, II, IV

d) I, IV

Q.7 S-ethylthiouronium can be converted to clonidine by reaction with?

a) Methyliodide

b) Ethylenediamine

c) Sufuric acid

d) Tryptophan amino acid

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ANSWERS

1-a

2-b

3-a

4-b

5-a

6-b

7-b

REFERENCES