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

Neostigmine

IUPAC nomenclature

[3-(dimethylcarbamoyloxy)phenyl]-trimethylazanium

Classification

  • Reversible anticholinestrase
  • Carbamates

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 223.29 g/mol
2 Physical appearance Solid
3 Melting point 144-149oC
4 Solubility Very soluble in water; soluble in alcohol
5 Octanol/water partition coefficient N/A
6 Presence of ring Phenyl
7 Number of chiral centers Not present

 

Mechanism of Action

  • Neostigmine increases the availability of the acetylcholine at the synapse by inhibiting acetylcholinestrase enzyme.
  • Acetylcholinestrase enzyme is responsible for the metabolism of acetylcholine, and thus, inhibition of acetylcholinestrase indirectly stimulates nicotinic and muscarinic receptors.

 

Structure Activity Relationship

General SAR for carbamates anticholinestrases can be summarized as follows:

  • Variation of the chain length influence AchE inhibition.
  • Most potent AChE inhibitor for the series was found to be having 7 methyl groups attached in the chain.
  • Replacement of the xanthone nucleus with other aryl groups decreases the AChE inhibitory activity.
  • Presence of polar group on the aromatic moiety is essential for the activity of drug.
  • If the flexible chain is replaced by the rigid linear ethyne group, activity of the drug is lost, which shows that, a flexible chain is necessary for the activity.
  • Introduction of the tertiary amino group into saturated ring decreases the activity, but activity is not fully lost.
  • Changing the length of the carbamic N-substituent has a significant effect on the selectivity of the drug. [1]

 

Method of synthesis

i. Reaction of 3-dimethylaminophenol and N-dimethylcarbonyl chloride to form dimethylcarbamate.

ii. Alkylation of the above formed compound using dimethylsulfate to get neostigmine.[2]

Medicinal Uses

Neostigmine is used for:

  • Treatment of myasthenia gravis 

 

Side Effects

Side effects of Neostigmine are:

  • Salivation
  • Fasciculation
  • Bowel cramps
  • Diarrhea
  • Allergic reactions
  • Dizziness
  • Vision changes
  • Convulsions
  • Drowsiness
  • Loss of consciousness
  • Headache
  • Dysarthria
  • Arrhythmia
  • Cardiac arrest
  • Hypotension
  • Respiratory depression
  • Bronchospasm
  • Respiratory arrest
  • Rash
  • Urticaria
  • Nausea
  • Vomiting
  • Muscle cramps
  • Flushing
  • Weakness 

 

 MCQs 

Q.1 Which statements are correct with respect to the physicochemical properties of drug Neostigmine?

I. Molecular weight:408.09gm/mol

II. Appearance: Solid

III. Melting point: 253oC

a) I, II

b) II

c) I, II, III

d) I, III

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

i. Neostigmine A. 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione
ii. Esmolol B. methyl (RS)-3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}propanoate
iii. Barbital C. (RS)-N’-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine

 

iv. Chloraquine               D. [3-(dimethylcarbamoyloxy)phenyl]-trimethylazanium

 

 a) i-C, ii-D, iii-A, iv-B

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

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

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

Q.3 Mechanism of action of Neostigmine includes?

I. Decreases the availability of acetylcholine at the synapse

II. Inhibition of acetylcholinestrases

III. Increase in metabolism of acetylcholine

IV. Indirect stimulation of muscarinic and nicotinic receptors

a) II, IV

b) I, II, III, IV

c) I, III

d) II, III, IV

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

  • Neostigmine: Carbamates anticholinestrase
  • Topotecan: Camptothecin analogues
  • 6-TG: Nitrosoareas alkylating agent
  • Methohexital: Inhalational anesthetics

a) TFFT

b) FTFT

c) TTTT

d) TTFF

Q.5 An incorrect statement related with the SAR of carbamates anticholinestrases is?

a) Variation of the chain length influence AchE inhibition.

b) Most potent AChE inhibitor for the series was found to be having 7 methyl groups attached in the chain.

c) Replacement of the xanthone nucleus with other aryl groups increases the AChE inhibitory activity.

d) Presence of polar group on the aromatic moiety is essential for the activity of drug.

Q.6 Type of ring present in the structure of Neostigmine?

I. Phenanthrene

II. Naphthaline

III. Phenyl

IV. Pyran

a) III

b) II, IV

c) I, III, IV

d) No ring structure present 

Q.7 Side effect of drug Neostigmine?

a) Bronchospasm

b) Loss of consciousness

c) Covulsions

d) All of the above

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ANSWERS

1-b

2-b

3-c

4-d

5-c

6-a

7-d

 

REFERENCES

[1] Rampa A, Piazzi L, Belluti F, Gobbi S, Bisi A, Bartolini M, Andrisano V, Cavrini V, Cavalli A, Recanatini M, Valenti P. Acetylcholinesterase inhibitors: SAR and kinetic studies on ω-[N-methyl-N-(3-alkylcarbamoyloxyphenyl) methyl] aminoalkoxyaryl derivatives. Journal of Medicinal Chemistry. 2001 Nov 8;44(23):3810-20.

[2] Vardanyan R, Hruby V. Synthesis of essential drugs. Elsevier; 2006 Mar 10.

 

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