Medicinal Chemistry of Opioid Analgesics 1; SAR of Phenolic -OH and 6 -OH

Question 1

What are the indications for opioid use?

List a few examples in each category.

Answer 1

• Moderate to severe pain (fentanyl, oxymorphone)
• Cough (codeine, ethylmorphine)
• Diarrhoea (loperamide, difenoxin)
• Opioid dependence (methadone, buprenorphine)

Question 2

What are common adverse reactions to opioids?

Answer 2

• Respiratory depression
• Nausea + vomiting
• Drowsiness
• Itching
• Dry mouth
• Miosis (excessive constriction of pupil)
• Constipation

Question 3

What are the three main issues with opioid use?

Answer 3

• Tolerance
• Physical dependence
• Addiction

Question 4

Where are δ receptors found?

Answer 4

CNS (brain), ENS (enteric nervous system)

Question 5

What is the agonist function of δ receptors?

Answer 5

• Analgesia
• Antidepressant
• Physical dependence (bad)

Question 6

Where are κ receptors found?

Answer 6

CNS (brain and spinal cord), ENS (enteric nervous system)

Question 7

What is the agonist function of κ receptors?

Answer 7

• Spinal analgesia
• Sedation
• Miosis (constriction of pupil)
• Inhibition of ADH (vasopressin) release

Question 8

Where are μ receptors found?

Answer 8

CNS (brain, spinal cord), ENS (enteric nervous system), GI (gastrointestinal)

Question 9

What is the agonist function of μ receptors?

Answer 9

μ1:

• Supraspinal (above the spine) analgesia
• Physical dependence

μ2 (BAD):

• Respiratory depression
• Miosis (pupillary constriction)
• Reduced GI motility

Question 10

What is a key detrimental agonist function of the nociceptin receptor, OP4?

Answer 10

• Tolerance to μ agonists.

Question 11

What does the multiple ring system of morphine confer?

Answer 11

It’s a rigid compound; locked, fused ring system.

Question 12

What does changing the phenolic -OH for e.g. CH3, Et, Acetyl mean for analgesic activity? (alkylation/acylation)

Answer 12

All lead to a decrease in analgesic activity.

Question 13

How does codeine have analgesic activity after replacing the phenolic -OH for a methyl group?

Answer 13

Codeine acts as a pro drug; the liver removes the CH3 in vivo = 20% morphine activity.

Question 14

What does changing the 6th -OH on the bottom cyclohexene ring for CH3, Et, Acetyl mean for analgesia? (alkylation/acylation)

Answer 14

• Modifications led to a 4-5 fold increase in activity

Question 15

How does acylating the 6 -OH (giving 6-acetylmorphine) confer greater analgesic activity?

Answer 15

• Replacing the 6 -OH for an acetyl group yielded greater lipophilicity than the (more) polar morphine molecule, crossing the BBB with ease (barrier to CNS receptors).

Question 16

Why is morphine (and its respective analogues) 80% ionised in the blood?

Answer 16

Morphine is a weak base; pKa 8.0. Therefore at physiological pH (7.4), it is mostly ionised/protonated, resulting in most of the dose residing in the blood.

Question 17

How does heroin (3, 6-diacetylmorphine) have greater analgesic activity than morphine even w/o the phenolic -OH?

Answer 17

Even though heroin is similarly 80% ionised in the blood, the twin acetyl groups (instead of -OHs) confer much greater lipophilicity; more of the unionised form can cross the BBB leading to a greater concentration at CNS receptors.

The acetyl groups attached at 3, 6 are then removed via esterases in the brain, leaving -OH again like the OG and resulting analgesic activity.

Question 18

Why is heroin not more active than 6-acetylmorphine given its more lipophilic?

Answer 18

6-acetylmorphine retains the phenolic -OH thus can express activity on μ receptors straight after crossing the BBB; heroin still has the acetyl group on the phenolic (3) -OH position to be removed via esterases first before being able to activate opioids.