CARVEDILOL Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

CARVEDILOL Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Carvedilol

IUPAC nomenclature

(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine

 

Classification

Carvedilol is a mixed α/ß blocker.

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 406.5 g/mol
2 Physical appearance Solid; forms colorless crystals from ethyl acetate
3 Melting point 114.5°C
4 Solubility Practically insoluble in water; freely soluble in dimethylsulfoxide; soluble in methylene chloride, methanol.
5 Octanol/water partition coefficient 3.8
6 Presence of ring Carbazol
7 Number of chiral centers 1

 

Mechanism of Action

  • Carvedilol inhibits ß-adrenoceptors which results in inhibition of the exercise induce tachycardia.
  • Smooth muscles in vasculature relaxes due to the action of carvadilol on α1-adrenergic receptors, which further results in reduced peripheral vascular resistance and an overall reduction in blood pressure.
  • Calcium channel blocking and antioxidant activity can also be seen at higher doses of the drug.
  • The antioxidant activity of drug prevents oxidation of low density lipoprotein and thus, prevents the uptake of same into coronary circulation. [1]

 

Structure Activity Relationship

  • The type of N-substitutions such as N-isopropyl and N-t-butyl eliminates α1-activity.
  • Arylalkyl groups with α-methyl substituent returns back the α­1-affinity but not the intrinsic activity.
  • The ß-blocking activity is almost 10-100 that of its α1-blocking activity. [2]

 

Method of synthesis

i. Condensation of 4-hydroxycarbazole with epichlorohydrin produces 4-(2,3-epoxypropoxy)carbazole.

ii. The latter compound is then reacted with 2-(2-methoxyphenoxy)ethanamine to produce carvedilol.[3]

 

Therapeutic Uses

Carvedilol is used for treatment of:

  • Hypertension
  • Prevention of strokes
  • Prevention of heart attacks
  • Prevention of kidney problems

Side Effects

Side effects of carvedilol are:

  • Dizziness
  • Tiredness
  • Impotency
  • Diarrhea
  • Drowsiness
  • Lightheadedness

MCQs

Q.1 Carvedilol inhibits exercise induce tachycardia through?

a) Agonism of α1-adrenergic receptors

b) Agonism of α2-adrenergic receptors

c) Antagonism of ß-adrenergic receptors

d) α-adrenergic antagonism

Q.2 Therapeutic use of drug Carvedilol is/are?

a) Glaucoma

b) Hypertension

c) Diabetes

d) All of the above

Q.3 Which amongst the following are the correct statements with respect to the SAR of drug Carvedilol-

I. The type of N-substitutions such as N-isopropyl and N-t-butyl eliminates α1-activity.

II. Arylalkyl groups with α-methyl substituent returns back the α¬1-affinity but not the intrinsic activity.

III. The ß-blocking activity is almost 1.5-folds that of its α1-blocking activity.

a) I, II

b) I, III

c) I, II, III

d) II

Q.4 The starting chemicals required for the synthesis of drug Carvedilol?

a) 2-(4-hydroxyphenyl-ethanol) and benzyl halide

b) Benzyl halide and epoxide

c) 4-hydroxycarbazol and epichlorohydrin

d) None of the above

Q.5 Correct sequence for the True/False for the physiochemical properties of the drug betaxolol-

I. Molecular weight = 307.4 gm/mol.

II. Melting point = 114.5°C

III. Octanol/water partition coefficient = 3.8

a) TFT

b) FFT

c) TTT

d) FTT

Q.6 Correct statements for the IUPAC nomenclatures of the drugs are?

I. Betaxolol: (RS)-1-{4-[2-(cyclopropylmethoxy)ethyl]-phenoxy}-3-(isopropylamino)propan-2-ol

II. Carvedilol: (RS)-1-{4-[(2-Isopropoxyethoxy)methyl]phenoxy}-3-(isopropylamino)propan-2-ol

III. Bisoprolol: (±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine

IV. Propranolol: (RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol.

a) I, II, IV

b) I, IV

c) III, IV

d) I, II, III, IV

 Q.7 Match the following drugs with their correct classifications-

i. Betaxolol A. ß1-ADRENERGIC AGONIST
ii. Carvedilol B. MIXED ACTING SYMPATHOMIMETICS
iii. Epinephrine C. MIXED α/ß BLOCKER
iv. Amphetamine D. NONSELECTIVE ADRENERGIC AGONISTS

 a) i-A, ii-C, iii-D, iv-B

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

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

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

 

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ANSWERS

1-c

2-b

3-a

4-c

5-d

6-a

7-a

  

REFERENCES

[1] Ruffolo RR, Gellai M, Hieble JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. European journal of clinical pharmacology. 1990 Mar 1;38(2):S82-8.

[2]  Lemke TL, Williams DA, Foye WO. Principles of medicinal chemistry. Williams & Wilkins; 2017, 361

[3] Vardanyan R, Hruby V. Synthesis of best-seller drugs. Academic press; 2016 Jan 7.

 

 

 

 

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