Page 229 - Medicinal Chemistry Self Assessment

2.24 Rivastigmine
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.

CH 3 C CH 3 D
A H C N O CH
3
N 3
O CH 3
2.24 Rivastigmine
218 Medicinal Chemistry Self Assessment B
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.
Rivastigmine

3. Rivastigmine is an acetylcholinesterase inhibitor. Inhibition of this enzyme prolongs the half-life of
1. Using the table CH 3 C CH 3 D
acetylcholine, allowing for higher concentrations of acetylcholine at muscarinic and nicotinic recep-
tors. This action is useful in the treatment of Alzheimer’s disease, myasthenia gravis, and glaucoma.
A
2. Based on their induction. CH N O CH 3
3
N
Shown below is the structure of acetylcholine interacting with the active site of acetylcholinesterase.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.
Glutamic acid, histidine, and serine are involved in the mechanism of ester hydrolysis and can form
specific interactions with acetylcholine. O CH 3

B
Labile ester bond Rivastigmine

1. Using the table
2. Based on their induction.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.

Labile ester bond

Rivastigmine

Acetylcholine bound to active site
of acetylcholinesterase

a. Conduct a structural analysis of rivastigmine and indicate how it could interact with acetylcholin-
Conduct a structural analysis of how it could interact with acetylcholinestase.
A.
esterase.
Answer:al groups to orient themselves in a similar manner within the enzyme binding site.
Rivastigmine
Answer

The structure of rivastigmine contains a tertiary amine that will be primarily ionized at a physi-
B
ological pH=7.4. This ionized amine mimics the quaternary nitrogen present within the structure
B
A
of acetylcholine and can form an ionic interaction with the glutamic acid or with the side chain
Acetylcholine bound to active site
A
of another acidic amino acid (comparison A). The carbamate present within the structure of
of acetylcholinesterase
rivastigmine is isosteric to the acetate ester of acetylcholine and thus can form similar hydrogen
bonds (comparison B). The distance between the tertiary amine and the carbamate of rivastig-
A.
Conduct a structural analysis of how it could interact with acetylcholinestase.
mine is two carbon atoms longer than the quaternary nitrogen and the acetate of acetylcholine;
Answer:al groups to orient themselves in a similar manner within the enzyme binding site.
however, conformational rotation within the structure of rivastigmine allows these functional
Key structural similarities
groups to orient themselves in a similar manner within the enzyme binding site.

B B
A
A
Key structural similarities
Similar distances after conformational rotation
(Note: The length of the lines are identical)

Similar distances after conformational rotation
(Note: The length of the lines are identical)