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

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

Ephedrine

IUPAC nomenclature

(1R,2S)-2-(methylamino)-1-phenylpropan-1-ol.

 

Classification

Ephedrine is a mixed adrenergic agonist.

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 165.23 g/mol
2 Physical appearance Present in waxy solid, crystals or granular form
3 Melting point 34 °C
4 Solubility Water solubility is 0.38M; it is soluble in oils.
5 Octanol/water partition coefficient 1.13
6 Presence of ring Benzene ring
7 Number of chiral centers 2

Mechanism of Action

  • Principle behind the mechanism of action of ephedrine is direct and indirect action on the adrenergic receptor system, which is actually, sympathetic nervous system.
  • Activity of post-synaptic is increased by the drug through directly activating post-synaptic α-receptors and ß-receptors.
  • The major action is due the inability of the pre-synaptic neuron to distinguish between real adrenaline and noradrenaline from ephedrine.
  • Ephedrine is uptake along with noradrenaline and packed in vesicles at the terminal button of the nerve cell.
  • Ephedrine’s action as an agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and to a lesser extent, serotonin by the same mechanism is presumed to have a major role in its mechanism of action. [1]

Structure Activity Relationship

 The SAR of Adrenergic agonist can be discussed as follows:

  • 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. Benzaldehyde is converted into levo-1-phenyl-2-keto-1-propano through fermentation.

ii.The above compound is then condensed with the help of methylamine and reduced with free aluminum in moist ether to give ephedrine.

Therapeutic Uses

Ephedrine is used:

  • For temporary relief from shortness of breath
  • During bronchial asthma
  • During chest tightedness

Side Effects

Side effects of propylhexedrine are:

  • Dizziness
  • Restlessness
  • Sleeplessness
  • Stomach irritation
  • Nervousness
  • Nausea
  • Headache
  • Allergic reaction

 MCQs

Q.1 Correct statements for the drug Ephedrine are?

I. Molecular weight is 165.23 gm/mol

II. Present in form of waxy solid

III.  It is having no ring in its structure

IV. Its melting point is 34°C

a) I, II, IV

b) I, IV

c) I, II, III, IV

d) I, II, IV

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

i. Ephedrine A. (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol
ii. Metaraminol B. 3-[(1R,2S)-2-amino-1-hydroxypropyl]phenol
iii. Pseudoephedrine C. (±)-1-cyclohexyl-N-methylpropan-2-amine
iv. Propylhexedrine D. (S,S)-2-methylamino-1-phenylpropan-1-ol.

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

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

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

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

Q.3 Principle behind mechanism f action of Ephedrine is?

a) Direct and indirect action on the adrenergic receptors

b) Direct action on the adrenergic receptors

c) Indirect action on the adrenergic receptors

d) No involvement of the adrenergic receptors

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

  • Ephedrine: Mixed adrenergic agonist
  • Propylhexedrine: α-adrenergic agonist
  • Pseudoephedrine: Nonselective adrenergic antagonist

 a) TTF

b) TFT

c) FTF

d) TTT

Q.5 Pick the correct statement related with the SAR of ephedrine.

a) When hydroxyl substituted carbon is in R configuration, activity is maximum.

b) When hydroxyl substituted carbon is in R configuration, activity is minimum..

c) Both configuration possess same activity.

d) Activity does not depend on the configuration of the hydroxyl substituted carbon.

Q.6 The correct sequence for the steps for synthesis of drug Ephedrine from benzaldehyde?

I. Condensation with methylamine

II. Reduction with Aluminium

III. Fermentation by yeast

a) I – II – III

b) II – III – I

c) I – III – II

d) III – I – II

Q.7 Side effect of drug Ephedrine is?

a) Dizziness

b) Restlessness

c) Nervousness

d) All of the above

 

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ANSWERS

1-d

2-a

3-a

4-a

5-a

6-d

7-d

 

REFERENCES

[1] Komissarov IV. The mechanism of action of ephedrine. Bulletin of Experimental Biology and Medicine. 1964 Apr 1;57(4):442-5.

[2] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 348-352

 

 

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