Medicinal Chemistry

Question 1

What functional groups does cocaine contain? (3)

Answer 1

2 ester groups
phenyl ring
tertiary amine

Question 2

What factors can cause hydrolysis of the ester groups in cocaine?

Answer 2

Extreme pH and boiling

Question 3

Cocaine is more soluble in chloroform (not so soluble in water), why is this so?

Answer 3

Ester groups are lipophilic

Question 4

Cocaine’s pKa is 8.6. What proportion of cocaine is protonated at physiological pH? (pH < pKa)

Answer 4

less than 50% protonated

Question 5

What are the essential groups for analgesic property? (3)

Answer 5

aromatic carboxylic ester
a basic amino group
a hydrocarbon ring

Question 6

Describe Soxhlet extraction

Answer 6

1. Leaves packed in thimble
2. Solvent evaporates and condenses onto porous thimble
3. Solvent extracts cocaine and leaves the porous thimble, accumulating in the solvent flask
4. Pure cocaine obtained by recrystallisation

Question 7

Which functional group was incorporated in the formation of lidocaine and what two properties was conferred?

Answer 7

Amide group

increases water solubility → more polar than esters
duration of action → C=N strong; extra methyl grp protects amide from water

Question 8

What are the 2 main classes of analgesics?

Answer 8

amino esters and amino amides

Question 9

How are amino esters synthesised? (2)

Answer 9

1. carboxylic acid (attached to phenyl ring/heterocycle) converted to acid chloride
2. Reacted w amino alcohol

Question 10

How are amino amindes synthesised? (2)

Answer 10

1. Aromatic amine (aryl/heteroaryl amine) reacts w carbonyl C to form amide
2. Nucleophilic substitution

Question 11

What 4 properties are important for the SAR of cocaine-derived local anesthetics?

Answer 11

1. Lipophilic portion essential for LA activity (facilitate permeation)
2. Intermediate chain should carry ester or amide then a 1-3 C chain (determines chemical stability and influences the duration of action)
3. The hydrophilic portion is either a secondary or tertiary amine, or the N should be part of a heterocycle
4. This amine should be basic and ionisable to give a cation, which helps facilitate its formulation as an injectable

Question 12

What is the relationship between lipid solubility and pKa on local anesthetic activity?

Answer 12

Higher lipid solubility and lower pKa = faster onset and lower toxicity

Question 13

What family of alkaloids are morphine and codeine obtained from?

Answer 13

Benzyltetrahydroisoquinoline

Question 14

What is the name of the 4 ring structure in analgesics?

Answer 14

Morphinan

Question 15

What do larger groups on top in morphine derivates mean?

Answer 15

More likely to be a receptor antagonist

Question 16

Why is pethidine the best choice for treating patients then sending them home?

Answer 16

Relatively low potency with relatively little respiratory depression effect

Question 17

Which drug is used as rescue therapy for heroin addicts?

Answer 17

Methadone

Question 18

What are the 2 metabolites of morphine

Answer 18

• 3-O-glucuronide: antagonistic to the analgesic effects of morphone
• 6-O-glucuronide is more effective and longer lasting as an analgesic than morphine with fewer side effects

Question 19

Which drug comes from morphine?

Answer 19

Codeine
m=Mono-O-methylation occuring at the acidic phenolic hydroxyl group

Question 20

How is Pentazocine structured? (omit and and keep what?)

Answer 20

omit ether bridge
keep cyclohexene rings with methyl groups

Question 21

How is pethidine structured? (which things to keep?)

Answer 21

retain aromatic ring and piperidine systems?

Question 22

What structure does fentanyl have (as compared to?)

Answer 22

4-anilino vs 4-phenyl-piperidine
(increases lipophilicity)

Question 23

What group is different in methadone?

Answer 23

Piperidine system is absend but the diphenylpropylamine can mimic the ring formation

Question 24

What kind of properties does nalbuphine show?

Answer 24

mixed agonist-antagonist properties
less side effects and abuse potential