Medicinal Chemistry of Opioid Analgesics 3; Development of Morphine Analogues Flashcards
What strategies are used to develop new analogues from the parent morphine molecule?
- Vary substituents
- Extend molecular structure
- Simplify
- Conformational/rotational restrictions
What did varying substituents (via phenolic alkylations) yield?
Alkylating the phenolic -OH led to poor/inactive compounds; the phenol is essential for activity (but the -OH at ‘6/on C-ring isn’t; glucuronidation in the body gives better analgesic)
What does extending molecular structure entail and why might it be beneficial?
Molecule is ‘extended’ by addition of potential extra binding groups; exploring receptor space outside of the parts that bind to the OG ligand.
Which position in morphine is it easiest to add substituents/what must be done first in order for this to occur?
- Nitrogen atom
- N-demethylation required first; methyl group needs to be removed to leave secondary amine
What is semi-synthesis and why is it used when developing morphine analogues (when extending molecular structure)?
- Using the OG compound extracted from natural sources as a starting point
- Used when parent compound too complex/expensive to completely synthesise (morphine requires 20 steps which results in poor yield anyway)
What is the rough outline of steps to achieve N-alkylated morphine from morphine?
- Reaction with chloroformate to make N into quaternary salt
- Resulting Cl- nucleophile attacks the methyl and removes it
- Treatment with methanol to cleave unwanted carbonate from earlier chloroformate yielding Normorphine
- Acylate with acid chloride yields N-acylated morphine
- Final reduction (removes ketone) gives N-alkylated morphine
How does agonist activity of the N-alkylmorphine increase with the size of the N-alkyl side chain?
- Methyl, Ethyl, Propyl = decreasing agonism
- Butyl = zero activity
- Pentyl, Hexyl = increasing agonist activity
Which N-alkyl group conveyed 14x activity of morphine and why is this so?
Phenethyl; binding to a new unrecognised hydrophobic binding pocket (van der Waals), extending the pharmacophore.
What was observed when an allyl (or cyclopropylmethyl) group was added for the N-alkyl? What other reactions were required to turn it into an antagonist?
- Very weak analgesic activity
- Oxidation of the 6-OH (superfluous) and reduction of the C7-8 double bond led to NALOXONE
»> No analgesic activity; pure antagonist.
What is the explanation for Naloxone’s antagonist activity?
- Naloxone stabilises the inactive receptor conformation, decreasing signal transduction hence unproductive G-protein coupling
- The allyl group is able to sit in the hydrophobic binding region when its in its inactive conformation; hydrophobic pocket is closed and closer to the allyl group as a result when receptor inactive; π electrons are able to interact wth it.
How does the N-phenethyl morphine analogue stabilise the active conformation of the receptor?
- The extra phenethyl group is able to sit comfortably in the open hydrophobic binding region observed when the receptor is in its active conformation; stabilising it and shifting the equilibrium towards the active conformation, increasing signal transduction.
What does Simplification occur when trying to find new morphine analogues and how might it be beneficial?
- Is entire molecular scaffold required?
- Lesser complexity = greater ease of synthesis
What does removal of the ‘E’ piperidine (N-containing) ring entail for analgesic activity?
Complete loss of activity (N essential)
What does removal of the ‘D’ ring (removal of cyclic ether/furan ring) entail for analgesic activity and what does it make?
- Creates MORPHINANS
- Possess analgesic activity; therefore ether bridge is not strictly essential
How do morphinans compare with OG morphine and what differs stereochemically?
- Morphinans display higher toxicity
- Comparable dependence profile
- Has 3 chiral centres instead of 5
