ic11 natural products Flashcards
what does coca contain (and other properties)
cocaine
cinnamoyl cocaine
tropacocaine
methyl ecgonine (minor constituent; product of partial hydrolysis of cocaine)
tropacocaine/benzoyltropine does not have a 2-methoxy group VS cocaine = abolish addiction liability.
what is tropane
fused bicyclic heterocycle
containing basic nitrogen
is an alkaloid
how to isolate cocaine from coca leaves
maceration
methods of purification for cocaine extract ? things to take note
soxhlet extraction to give concentrated extract (use a solvent with lower boiling point; use a non polar solvent so non polar solvents will be extracted, ie will be dissolved in the solvent to be siphoned)
> column chromatography
cocaine analgesic effect?
blocking sodium channel upon permeating across the neuronal membrane
pka and effect on cocaine
cocaine is basic (8.6 pH)
at physiological ph it will be ionised (90%); remaining 10% moves through membrane = causing equilibrium shift, more will be converted
if e.g., intracellular membrane is lower pH, almost all will be ionised = interact w the sodium channel
what are the essential functional grps for cocaine analgesic action?
aromatic carboxylic acid ester
basic amino group
lipophilic hydrocarbon ring
benzocaine structural modification
good anesthetic property,
low toxicity
low water solubility
procaine structural modification
replacement of tropine with amine
strong local anesthetic property but short duration of action
lidocaine properties
amide derived from isogramine SAR
less allergenic, more stbale in water, good local anesthetic
amide group confers longer duration of action due to minor double bond character (from delocalisation)
AND
presence of two methyl groups (of tertiary amine) = block water from entering = less likely to hydrolysed
what is needed for analgesia activity from cocaine derivatives
1) lipophilic portion
- needed for long-acting activity = facilitates permeation
2) intermediate chain (should carry ester or amide + 1-3 carbon chain)
- chain length determines chemical stability = duration of action
- cannot be too long or it will reduce LA activity
- amide > ester = also determines stability
3) hydrophilic portion
- 2º or 3º amine
- heterocycle N = helps to increase lipophilicity to permeate membrane
- should be basic and ionisable to give cation
high lipid solubility and lower pKa = faster onset and lower toxicity
what does high lipid solubility mean?
log P = C unionised, non polar ÷ C unionised, polar. Low logP = more hydrophilic.
log D = C unionised, non polar ÷ C total drug, polar. Affect by pH.
what is the ideal local anesthetic agent
MOA:
1) reversible blockade
2) selective for sensory neurons (no effect on motor neurons)
PK
3) rapid onset
4) sufficient DOA
Safety
5) no systemic toxicity
6) wide margin of safety
7) compatible w/ other co-administered drugs
8) absence of ADR
Final Product
9) chemically stable when sterilised (not degradation from heat)
10) inexpensive
what is morphine
alkaloid of poppy plant latex from the class of benzyl tetrahydroisoquinoline = produce morphine
morphine metabolism and properties
metabolised to 3-o-glucuronide and 6-o-glucuronide, of which the 3-o one is antagonistic to the analgesic effects of morphine while the 6-o one is more effective and longer lasting analgesic (with less side effects)
what is codeine and how it is made
3-O-methyl ether of morphine
has 1/10 potency of morphine
- non addictive (but still constipating in long term)
- antitussive action (for coughing)
via semi-synthesis with mono-O-methylation at the 3º acidic phenolic hydroxy group of morphine
what is semi synthesis and relation of morphine derivatives
semisynthesis used to create analogues of natural proteins via chemical manipulation.
only individually purified opium alkaloids and their derivatives are used clinically.
semisynthesis of morphine
alkylation (sn2 reaction) with N-chloroethylmorpholine = pholcodine (antitussive)
catalytic reduction of double pond at position 7 & 8 = dihydrocodeine (similar analgesic)
diacetate at 6-oh and 3-oh = diamorphine (highly addictive analgesic and hypnotic due to increased lipophilic character = better transport and absorption)
synthetic opioid drugs
1) pentazocine (analgesic, non addictive w/ withdrawal sx)
- ether bridge omitted
- cyclohexene ring replaced w/ simple methyl groups
2) pethidine (short acting analgesic, less constipating but addictive)
- only aromatic ring, piperidine system retained.
3) fentanyl, alfentanil, remifentanil
- 4-anilino instead of 4-phenyl-piperidine structure
4) tramadol
main concept for efficacy of opioid drugs
degree of lipophilicity and transport property
retained pharmacophore
active conformation
