Medicinal Chemistry of Opioid Analgesics 1; SAR of Phenolic -OH and 6 -OH Flashcards
What are the indications for opioid use?
List a few examples in each category.
- Moderate to severe pain (fentanyl, oxymorphone)
- Cough (codeine, ethylmorphine)
- Diarrhoea (loperamide, difenoxin)
- Opioid dependence (methadone, buprenorphine)
What are common adverse reactions to opioids?
- Respiratory depression
- Nausea + vomiting
- Drowsiness
- Itching
- Dry mouth
- Miosis (excessive constriction of pupil)
- Constipation
What are the three main issues with opioid use?
- Tolerance
- Physical dependence
- Addiction
Where are δ receptors found?
CNS (brain), ENS (enteric nervous system)
What is the agonist function of δ receptors?
- Analgesia
- Antidepressant
- Physical dependence (bad)
Where are κ receptors found?
CNS (brain and spinal cord), ENS (enteric nervous system)
What is the agonist function of κ receptors?
- Spinal analgesia
- Sedation
- Miosis (constriction of pupil)
- Inhibition of ADH (vasopressin) release
Where are μ receptors found?
CNS (brain, spinal cord), ENS (enteric nervous system), GI (gastrointestinal)
What is the agonist function of μ receptors?
μ1:
- Supraspinal (above the spine) analgesia
- Physical dependence
μ2 (BAD):
- Respiratory depression
- Miosis (pupillary constriction)
- Reduced GI motility
What is a key detrimental agonist function of the nociceptin receptor, OP4?
- Tolerance to μ agonists.
What does the multiple ring system of morphine confer?
It’s a rigid compound; locked, fused ring system.
What does changing the phenolic -OH for e.g. CH3, Et, Acetyl mean for analgesic activity? (alkylation/acylation)
All lead to a decrease in analgesic activity.
How does codeine have analgesic activity after replacing the phenolic -OH for a methyl group?
Codeine acts as a pro drug; the liver removes the CH3 in vivo = 20% morphine activity.
What does changing the 6th -OH on the bottom cyclohexene ring for CH3, Et, Acetyl mean for analgesia? (alkylation/acylation)
- Modifications led to a 4-5 fold increase in activity
How does acylating the 6 -OH (giving 6-acetylmorphine) confer greater analgesic activity?
- 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).
Why is morphine (and its respective analogues) 80% ionised in the blood?
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.
How does heroin (3, 6-diacetylmorphine) have greater analgesic activity than morphine even w/o the phenolic -OH?
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.
Why is heroin not more active than 6-acetylmorphine given its more lipophilic?
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.
