Chemistry 1 Flashcards
Need to finish lecture 4 plus SAR
What are opium alkaloids?
Examples of opium alkaloid drugs
What type of analgesics are opium alkaloids?
Centrally acting analgesics
Strong Narcotic effect
Opium alkaloids have a strong ______ effect?
What does it mean?
How many opioid compounds have been approved?
>50
Clinical use of opioids
Mainly used for their analgesic properties in the management of acute + chronic pain
- Moderate - severe pain e.g. fentanyl
- Cough e.g. codeine
- Diarrhoea e.g. loperamide
- Opioid dependance e.g. methadone
Name ADRs of opioids
Describe the problem of opioid use
Tolerance leads to physical dependance, which leads to addiction
How is codeine converted to morphine?
Name the 3 major subtypes of opiate receptor
Which opiate receptor is common?
Mu-opioid receptor
Delta agonist function
Mu1 agonist function
Supraspinal analgesia + physical dependance
Mu2 agonist function
Kappa agonist function
Agonist function of nociceptor
Name the body’s natural painkillers + where they are produced
Name the 6 stages of narcotic analgesic development
Shape + no. of rings in morphine structure
How do we test analgesics?
In vivo (in living organism)
Why does in vivo analgesia decrease?
What prohibits CNS receptor access?
How comes heroin can enter CNS easier than morphine?
How many chiral centres does Morphine have?
Why is morphine’s enantiomer completely inactive?
What is epimerisation?
What is pharmacophore?
Draw common metabolic reactions of morphine
What functional group does Mu-receptor agonist have and how is it dealkylated?
Mu-receptor have an N-methyl group which is dealkylated by CYP3A4
Why are non-metabolites limited therapeutically?
Why do some patients not respond to codeine-based analgesics?
Phase 2: What do phenols conjugate with?
What type of patients have those conjugates found in their urine + are they active?
Phenols conjugate with either glucuronic acid or sulfate
Both conjugates found in urine of patients taking multicyclic opioids
Mainly inactive
Phase 2 conjugation impacts on _______
What has a higher potency than morphine + by how much?
What is a drawback of M6G?
What are the 4 strategies for morphine analogue development?
What is vary substituents?
Describe molecular structure
- What is the easiest position to add substituents?
- What does semi-synthesis require?
*
Draw synthesis of N-alkylated morphine analogues
Functionalisation of 2ndary amine using alkyl halides leads to a range of N-alkylmorphines
What alkyl morphines cause:
- increase in antagonism?
- 0 activity?
- agonists?
- 14x activity of morphine?
How was Naloxone produced?
What is the clinical use of Naloxone?
In simplification, _____ complexity causes ________ of synthesis
Which 5 rings in the morphine skeleton has no activity if it is removed?
E
Name structure if:
- D is removed?
- C + D is removed?
- B, C + D is removed?
- B, C, D + E is removed?
All of the rings above have been removed but which one has a rapid onset of analgesic action but short onset?
Which levorphanol isomer has little/no activity?
(+) isomer
If we want to extend morphine, what do we add to form a:
- antagonist?
- increase activity?
Antagonist = allyl on N
Increase activity = phenethyl
Which simplified morphine analogue causes higher toxicity than morphine?
Example of a 4-phenylpiperidine + describe clinical use
Name a successful piperidine derivative + explain why it is good
Fentanyl
100x > potent than morphine
Lacks OH in phenol but still lipophilic
Which methadone isomer is active?
Where is methadone’s chiral centre?
What is the clinical use of methadone?
Why is methadone marketed in its racemic form?
What is the clinical use of methadone’s S(+) isomer + how does this lead to its serious side effects?
Methadone has a prolonged duration of action.
Why is this?
How is methadone administrated?
Orally or Injection
A patient has difficulty swallowing orally.
How can they be administered methadone?
Swish + spit
Patients who struggle swallowing oral dosage forms use methadone with alkalinising agent to increase saliva pH from 6.4 - 8.5
If solution is held in mouth for 2 and a half minutes, buccal absorption of 85% is achieved
What opioid receptor does tramadol use?
Who cannot take tramadol + why?
What racemic isomer form is tramadol marketed + why?
Racemic mixture of Cis-Isomers
(1R, 2R) enantiomer > 30x potent than (1S, 2S)
Racemic formulation displays tolerability
Describe tramadol metabolism
O-demethylated via CYP2D6 metabolism to more potent opioid (200 fold increase)
How are oripavines made?
What are conformational restrictions?
What is the diers-alders reaction?
Concerted cycloaddition reaction between diene + dienophile to form 6-membered ring containing double bond
How are oripavines formed?
Examples of oripavines
How was buprenorphine made?
How is buprenorphine formulated?
Difference between Etorphine + Morphine
Clinical use of Etorphine
