The Medicinal Chemistry of Opioid Analgesics 3 Flashcards
What is the effect on extending the molecular structure of morphine?
Potentially adding further binding sites to the molecule
Where is the easiest place to add substituents to the morphine structure?
Nitrogen atom
What is semi-synthesis?
Starting with a natural molecule and adding to it / precursor is too complex for natural synthesis
How do we produce N-alkylated morphine?
Morphine and chloroformate are mixed together. The lone pair from the N attack the =O and the lone pair is added to the Cl which leaves.
The Cl can then attack the methyl group (as the smallest, it is cleaved).
Acid chloride and alkyl halides added which leads to production of N-alkylated morphine and N-acetylated morphine
What happens when you add a aryl to the N atom of the tertiary amine?
Produce N-alkylmorphines
Me–>Et–>Pro agonism is decreasing
Butyl shows no agonism at all
Pent–>Hexyl –> Phenyl shows increasing agonism
Phenethyl group shows 14x activity than morphine
Why does the addition of a phenethyl group increase analgesic activity?
Probably binds to an unrecognised hydrophobic pocket
What happens to morphine if an allyl or cyclopropylmethyl group is attached to the N atom?
Allyl - naloxone produced, possesses no analgesic affect, is a direct antagonist and is used for treatment of opioid overdose
Why is it beneficial to reduce the complexity of a drug structure?
Easier to synthesise
How does the removal of ring E affect morphine activity?
Ring E contains the nitrogen atom that is essential to action
How does the removal of ring D affect morphine activity?
Upon removal of ring D includes the cyclic ether (furan ring) the molecule still has analgesic effect
Morphinans - therefore ether bridge is not essential
Give an exampple of a commonly used morphinan
Levorphanol has the structure of morphine minus the D ring and is 5x more potent than morphine
The (+)-enantiomer of levorphanol (dextrophan) has insignificant analgesic properties but is used as an anti-tussive
DEXTROMETHORPHAN
What happens when a phenethyl group is added to the nitrogen of the morphine structure?
Increased analgesic activity
What happens when ring D (furan ring) and ring C are removed?
Benzomorphans produced - tricyclic system
Removal of furan insignificant and removal of -OH alcohol and the double bond insignificant also
Therefore retain analgesic activity
