The Medicinal Chemistry of Opioid Analgesics 3 Flashcards Preview

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Flashcards in The Medicinal Chemistry of Opioid Analgesics 3 Deck (13)
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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


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