Medicinal Chemistry

Question 1

Why is cocaine classified as an alkaloid?

Answer 1

Natural product derived
Contains nitrogen in a fused tropane ring
Basic in nature

Question 2

What functional groups are present in cocaine?

Answer 2

Tropane ring with basic tertiary amine in the fused bicyclic heterocycle (hydrophilic)

2 ester groups (intermediate chain and addictive potential)

Aromatic part (Benzene, lipophilic)

Question 3

What will result from the hydrolysis of cocaine?

Answer 3

Ecgonine, methanol and benzoic acid

Question 4

Cocaine has a pKa of 8.6. Which is the ionizable group?

Answer 4

Tertiary amine in the tropane ring

Question 5

How does the pKa favor permeation across membrane and binding to sodium channels?

Answer 5

Unionized at pH 7.4: Permeate across lipophilic phospholipid membrane (Only 10% ionized)

50% ionized when pH = pKa: Favor binding to sodium channel

Question 6

What SAR strategies were adopted in cocaine?

Answer 6

Simplification to Tropacocaine (Benzoyltropine) - Remove carbomethoxy group
- Remove addictive potential

Analoguing to Procaine and Benzocaine
- Substituting the tropane ring
- Procaine (Amine): Stronger anesthetic, less toxic, more water solubility
- Benzocaine: Strong anesthetic, less toxic

Question 7

What is the SAR strategy for isogramine to lidocaine?

Answer 7

Simplification by ring opening

Question 8

What gives lidocaine better water solubility?

Answer 8

The inclusion of the amide

Question 9

What structural features in lidocaine contribute to longer action compared to procaine?

Answer 9

Presence of amide in lidocaine compared to ester in procaine makes it less susceptible to hydrolysis

Presence of methyl group blocking the amide from hydrolysis

Question 10

What is the benefit of lidocaine?

Answer 10

Less allergenic
More stable in water

Question 11

How do the lipophilic and hydrophilic portions facilitate local anesthetic activity?

Answer 11

Lipophilic aromatic part: Permeation and lower toxicity

Length and type of intermediate chain: Chemical stability (Amide) and LA activity (Too long will reduce it)

Hydrophilic amino group: Basic and ionizable. Lower pKa facilitate faster onset

Question 12

What is the class of opium alkaloids?

Answer 12

Benzyltetrahydroisoquinoline

Question 13

Opium alkaloids have what SAR?

Answer 13

Morphinan ring

Question 14

How does the modification of the morphinan ring improve the opium drug?

Answer 14

Simplification by ring opening

Less structural rigidity and can still perform the same action (Methadone vs morphine)

Less euphorigenic effects