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

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

Methacholine

IUPAC nomenclature

2-(Acetyloxy)-N,N,N-trimethylpropan-1-aminium.

Classification

Methacholine is a cholinergic agonist falls in the class of choline esters.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 160.23 g/mol
2 Physical appearance Present in solid form
3 Melting point 171-173°C
4 Solubility Water solubility is 0.0947mg/ml
5 Presence of ring Not present
6 Number of chiral centers 1

 

Mechanism of Action

  • Methacholine induces bronchoconstriction by agonizing the muscarinic receptors.
  • Therefore, this is used during the test of asthma and bronchial hyperreactivity.

 

Structure Activity Relationship

  • When the nitrogen of the quaternary ammonium group is replaced with arsenic, phosphorous, sulfur or selenium, their activity decreases.
  • It is necessary for the atom present at the nitrogen position to have a positive charge to have muscarinic activity.
  • When all three methyl groups are replaced by larger alkyl groups at the quaternary nitrogen, drug becomes inactive as agonist.
  • When all the methyl groups associated with the quaternary nitrogen atom are replaced by ethyl groups, the compound becomes cholinergic antagonist.
  • Replacement of just one methyl group associated with quaternary nitrogen with an ethyl or a propyl group gives the compound which is having lesser activity than acetylcholine.
  • Substitution of the methyl groups associated with quaternary nitrogen with hydrogen atoms also leads to diminishing of the muscarinic activity.
  • At the ethylene bridge, synthesis of acetic acid esters of quaternary ammonium alcohols of greater length than choline led to a series of compounds which are having lesser activity as the length of the chain increases.
  • There should be no more than 5 atoms between nitrogen and terminal hydrogen to have the maximum muscarinic activity.
  • Replacement of the ethylene bridge by the alkyl groups larger than methyl groups decreases the activity.
  • The R-(-) isomer is 20 time less potent.
  • For the maximum potency, the alkyl groups at the nitrogen atoms should not be larger than methyl groups.
  • Presence of oxygen in an ester form increases the activity.
  • For maximum activity, there should be two- carbon atoms between the nitrogen and oxygen atom. [1]

 

Method of synthesis

i. Addition of trimethylamine to propylene chlorohydrins gives (2-hydroxypropyl)trimethylammonium ion.

ii. The latter compound on reaction with acetic anhydride forms methacholine.

 

Therapeutic Uses

Methacholine is used for test of:

  • Asthma
  • Bronchial hyperreactivity

 

Side Effects

Side effects of methacholine are:

  • Dizziness
  • Nausea
  • Vomiting
  • Lightheadedness
  • Sore throat
  • Headache

MCQs

Q.1 Correct statements related with the Physicochemical properties of Methacholine are?

I. Molecular weight = 160.23 gm/mol

II. Physical appearance : present in viscous liquid form

III. Melting point = 35°C

IV. Solubility: very soluble in water 

a) I, III

b) I, II, IV

c) II, IV

d) I

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

i. Methacholine A. 2-(Acetyloxy)-N,N,N-trimethylpropan-1-aminium.
ii. Homatropin B. (RS)-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate
iii. Procyclidine C. (N-Methyl-8-azabicyclo[3.2.1]oct-3-yl) 2-hydroxy-2-phenylacetate
iv. Atropin D. 1-cyclohexyl-1-phenyl-3-pyrrolidin-1-ylpropan-1-ol

 a) i-B, ii-A, iii-D, iv-C

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

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

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

Q.3 Correct steps for the mechanism of action of the drug Methacholine?

I. Antagonizing muscarinic receptors

II. Agonizing muscarinic receptors

III. Induction of bronchoconstriction

a) I – III

b) II – III

c) III – I

d) III – II

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

  • Methacoline: Cholinergic antagonist
  • Procyclidine: Muscarinic antagonist
  • Homatropin: Cholinergic agonist
  • Atropin: Muscarinic antagonist

a) FTFT

b) TTTF

c) TFTF

d) FFTT

Q.5 Number of atoms requires between nitrogen and terminal hydrogen to have maximum activity for Methacholine is?

a) 1

b) 4

c) 5

d) 7

Q.6 The correct sequence for the steps for synthesis of drug Methacholine from Propyline chlorohydrine?

I. Reaction with trimethylamine

II. Reaction with acetic anhydride

III. Reduction

IV. Oxidation

a) I – II

b) I – III – II

c) I – III – II – IV

d) III – II – IV

Q.7 Side effect of drug Methacholine?

a) Dizziness

b) Sore throat

c) Lightheadedness

d) All of the above

 

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ANSWERS

1-d

2-b

3-b

4-a

5-c

6-a

7-d

 

 

REFERENCES

[1]  Lemke TL, Williams DA, Foye WO. Principles of medicinal chemistry. Williams & Wilkins; 2017, 320.

 

 

 

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