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

Gabapentin

IUPAC nomenclature

1-(Aminomethyl)cyclohexaneacetic acid

Classification

Gabapentin is an anticonvulsant drug.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 171.24g/mol
2 Physical appearance White to off-white crystalline solid
3 Melting point 162-166°C
4 Solubility Freely soluble in water, alkaline and acidic solutions.
5 Octanol/water partition coefficient 1.25
6 Presence of ring Cyclohexyl ring
7 Number of chiral centers Not present

 

 

Mechanism of Action

Gabapentin inhibits the action of α2δ-1 subunits. Due to this, there is decrease in density of pre-synaptic voltage-gated calcium channels and subsequent release of excitory neurotransmitters. This inhibition is also responsible for the anti-epileptic action of the drug.

 

Structure Activity Relationship

  • Substitution of the isopropyl group with diethyl decreases affinity for α2δ by more than 15 fold.
  • 1-ethylpropyl analogues are 2.5 fold weaker at α2δ but having the same potency at inhibiting system L transport of leucine.
  • Transposition of the isobutyl side chain to the C-2 position reduces affinity for α2δ and system L transporter. Changes also led to loss of in vivo activity in the epilepsy, pain and anxiety models.
  • Substitution of a methyl group α to the carboxylic acid leads to complete loss of affinity for α2δ subunit. There is little effect on system L transporter affinity.
  • Substitution with methyl or ethyl groups at C-3 position causes 40 to 100-fold decrease in α2δ affinity and 3 to 5-fold increase in affinity for system L transporter.
  • Introduction of a methyl group α to the amine group and trans to the 3-isobutyl group enhances the α2δ affinity by 2-fold and decrease in system L transport potency.
  • Original isobutyl side chain is optimal side chain at the C-3 position.
  • Introducing the methyl group α to the amine in a syn orientation increases potency of α2δ by 2-folds while, there is complete loss of activity at the system L amino acid transporter. [1]

 

Method of synthesis

i. 1,1-cyclohexane diacetic acid anhydride is converted to 1,1-cyclohexane diacetic acid monoamide by reacting the former with a composition that produces free ammonia in solution

ii. 1,1-cyclohexane diacetic acid monoamide undergoes Hoffmann reaction to produce gabapentin. [2]

Therapeutic Uses

Gabapentin is used for:

  • Prevention and control of seizures
  • Relieving nerve pain

 

Side Effects

Side effects of Gabapentin are: 

  • Dizziness
  • Drowsiness
  • Blurred vision
  • Double vision
  • Tremors
  • Depression
  • Suicidal thoughts
  • Mood changes

 

MCQs 

Q.1 Choose the correct statements related with the physicochemical properties of drug Gabapentin.

I. Molecular weight = 278.19 gm/mol

II. It is white to off-white crystalline solid

III. Melting point is 215oC

IV. It is freely soluble in water

a) I, III, IV

b) II, IV

c) I, IV

d) I, II, IV

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

i. Gabapentin A. 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
ii. Loxapine    B. 5H-dibenzo[b,f]azepine-5-carboxamide
iii. Carbamazepine C. 1-(Aminomethyl)cyclohexaneacetic acid
iv. Thiopental D. 5-ethyl-5-pentan-2-yl-2-sulfanylidene-1,3-diazinane-4,6-dione

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

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

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

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

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

I. Inhibition of the action of α2δ-1 subunits

II. Stimulation of the action of α2δ-1 subunits

III. Increase in density of pre-synaptic voltage-gated calcium channels

IV. Decrease in density of pre-synaptic voltage –gated calcium channels

a) I – IV

b)II – III

c) III – I

d) IV- II

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

  • Gabapentin: Anticonvulsant drug
  • Metocurine: Muscarnic agonist
  • Cevimeline: Acetylcholine antagonist
  • Succinylcholine: Nicotinic antagonist

a) TFFT

b) TTTT

c) TFFT

d) FFTF

Q.5 Original isobutyl side chain of the gabapentin is?

a) Optimal at C-2 position

b) Optimal at C-3 position

c) Produces optimal activity at C-5 position

d) Produces optimal activity at C-4 position

Q.6 Correct steps for the synthesis of gabapentin from 1,1-cyclohexane diacetic acid anhydride are?

I. Reduction

II. Hoffman reaction

III. Reaction with free ammonia

IV. Treatment with Baeyer’s reagent

a) II, IV

b) II, IV

c) I, III

d) III, II

Q.7 Side effect of drug Gabapentin include?

a) Hyperactivity

b) Shallow breathing

c) Increase in blood counts

d) Tremors

 

 

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ANSWERS

1-b

2-a

3-a

4-a

5-b

6-d

7-d

 

REFERENCES

[1] ] Belliotti TR, Capiris T, Ekhato IV, Kinsora JJ, Field MJ, Heffner TG, Meltzer LT, Schwarz JB, Taylor CP, Thorpe AJ, Vartanian MG. Structure− activity relationships of Pregabalin and analogues that target the α2-δ protein. Journal of medicinal chemistry. 2005 Apr 7;48(7):2294-307.

[2] Kumar A, Soudagar SR, Nijasure AM, Panda NB, Gautam P, Thakur GR, inventors; Ipca Laboratories, assignee. Process For Synthesis Of Gabapentin. United States patent application US 11/923,352. 2008 May 1.

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