Methacholine is a cholinergic agonist falls in the class of choline esters.
|S. NO.||PHYSICAL AND CHEMICAL PROPERTIES|
|1||Molecular weight||160.23 g/mol|
|2||Physical appearance||Present in solid form|
|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. 
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.
Methacholine is used for test of:
- Bronchial hyperreactivity
Side effects of methacholine are:
- Sore throat
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
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
Q.5 Number of atoms requires between nitrogen and terminal hydrogen to have maximum activity for Methacholine is?
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
a) I – II
b) I – III – II
c) I – III – II – IV
d) III – II – IV
Q.7 Side effect of drug Methacholine?
b) Sore throat
d) All of the above
REFERENCES Lemke TL, Williams DA, Foye WO. Principles of medicinal chemistry. Williams & Wilkins; 2017, 320.