Dugga 3- opioid analgesics Flashcards
What does analgesic mean?
To relieve pain
What are opioids?
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia.
What type of receptors are opioid receptors?
G protein coupled receptors
What does morphine look like?
Four six membered rings (3 planar and one perpendicular to it), two OH groups, One NMe group and an oxygen bound by two six membered rings forming a five-membered ring
Does opium contain morphine?
Yes
What are the important groups in morphine?
OH group, aromatic ring and tertiary amine (protonated and ionised when drug interacts with binding site)
Is morphine a chiral molecule?
Yes it contains several assymmetric centres
What are the side effects of morphine?
Dependence, depression and tolerance
What are the three types of analgesic or opioid receptors activated by morphine?
mu, kappa and delta receptors, all G protein coupled receptors
Which functional groups are important and why?
the amine nitrogen is protonated and charged which means it forms ionic bonds,
the phenol acts as hydrogen bond donor,
the aromatic ring has a defined orientation allowing van der Waals interactions with a hydrophobic location in the binding site
Where are the analgesic receptors located?
In the central nervous system (so morphine needs to cross BBB)
How does a polar molecule such as morphine cross BBB?
The amine group is a weak base so morphine exists both as free base and ionised form and the free base can cross BBB and then be ionised to interact with opioid receptors
What is another name for diamorphine?
Heroin
Which prodrugs of morphine exist and why?
6-acetylmorphine (4x more active) and diamorphine (2x more active), the polar functional groups are masked and it is then possible to get increased levels of morphine in the brain
Which receptor does morphine bind most strongly to?
The mu receptor (this is responsible for the serious side effects of morphine)
Which receptor is responsible for analgesia and sedation (but has psychological side effects)
Kappa
Which receptor is favoured by enkephalins?
The delta receptor
Can opioids also be used to treat diarrhea?
Yes, because a side effect of them is constipation so morphine analogues have been developed that focus only on improving that side effect. Names of these drugs ae loperamide, imodium and diphenoxylate
What is enkephalin?
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body’s opioid receptors.
What does an addition of a 14hydroxyl group or an N-phenethyl group do to morphine?
Increases activity as a result of interactions with extra binding regions
How are N-alkylated analogues of morphine synthesised?
By demethylating morphine to normorphine and alkylating with alkyl halides
What happens to morphine structures when suitable N-substituents are added?
Compounds act as antagonists or partial agonists
Why can small changes in morphin analogues result in it being an agonist or antagonist?
It is proposed that there are two accessory hydrophobic regions and an agent will act as an agonist or antagonist depending on which region it reaches
Which peptides act as the body’s natural painkillers?
Enkephalins, dynorphins, endomorphins and endorphines
What is crucial to the activity of the peptides that act as the body’s own painkillers?
The N-terminal tyrosine
How have analogues of enkephalin been made more stable?
More stable to peptidases by the inclusion of unnatural amino acids, D-amino acids or N-methylated peptide links
Which concept has been used to design opioids that are selective for a particular type of opioid receptor?
Message-address concept.
What are alkaloids?
Plant-derived nitrogen containing compounds (are bases/alkaline)
Which strategies exist to make analoges?
Vary substituents
Extend structure
Simplify structure
Rigidify structure
Do we need the SAR before making analogues?
Yes
Extending stucture can improve binding in what way?
Extra binding groups
Extending the structure can also lead to the formation of …
antagonists
Which rings are essential in morphin?
Ring A and E
What is fentanyl?
A morphin analogue 100x stronger than heroine, used in hospitals, given in very controlled amount
What is the opioid epidemic?
People in US became dependent on opiate agonist called oxycontin
Is ring E really essential for morphine?
No, can be mimicked by phenyl and methyl
Give an example of a morphine analogue without ring E?
Metadon
Used to treat heroin addiction
