ic11 natural products Flashcards
what is the water solubility of cocaine
poor water solubility
in ethanol, solubility is 1g/6.5ml
in chloroform, solubility is 1g/0.7ml
in ether, solubility is 1g/3.5ml
in water, solubility is 1g/600ml
what class of drug is cocaine and why is it an alkaloid and where is cocaine found
cocaine belongs to the class of tropane alkaloid
tropane is a fused bicyclic heterocycle containing a basic N and is an alkaloid
cocaine is found mainly in erythroxylum cocoa
what structure does cocaine have and what is the significance of its structure (relate to other structures also derived from cocoa)
cocaine is rapidly absorbed by mucus membrane and paralyses peripheral and sensory nerves by blocking ion channels in neuron membranes
cocaine binds to dopamine receptors which decr the reuptake of dopamine and results in a buildup of dopamine in the synapse thus there is an amplified signal to its receiving neurons, creating the euphoria
cocaine has a carboxymethoxy group at pos 2 and an ester at pos 3 which undergoes hydrolysis after being rapidly absorbed by mucus membrane to form ecognine (and benzoic acid and methanol)
removing carboxymethoxy group at pos 2 (aka tropacocaine) can help to remove its addiction liability
other structures derived from cocoa incl tropacocaine, cinnamoylcocaine, methylecognine
what is the set up for the process of cocaine extraction
soxhlet apparatus (comprising of extraction thimble, siphon tube and percolator), with reflux condenser and boiling flask (containing extraction solvent) attached at top and bottom respectively
EXTRACTION PROCESS
*CONTINUOUS PROCESS
1. cocoa leaves are packed into the extraction thimble (which is made up of methyl cellulose and is porous)
2. solvent evaporates (after being subjected to heat) and condenses into the thimble, leaves soak up the solvent
3. solvent that was absorbed extracts the cocaine and since thimble is porous, whatever that is extracted will seep through the walls of the thimble and goes to outside of the extraction thimble
4. as volume of solvent increases the level of solvent moves up and upon reaching past the arch of siphon tube, it will drain back into the round bottom flask
5. crude cocaine is obtain through rotatory evaporation (placing round bottom flask into the rotatory evaporator and subject it to be under vacuum to extract the solvent, solvent ends up in receptor and residual is still in initial round bottom flask (residue is the component extracted from the leaves of the natural product)
6. recrystallisation to obtain pure cocaine (or purification through HPLC) -> residue is tested in various assays
the longer the set up runs for, the deeper the colour in the sample extract bc more constituent extracted
solvents used incl: volatile ROH (ethanol, methanol), chloroform, ethyl acetate, hexane, water (tho not very ideal bc can cause hydrolysis of cocaine)
what is the rationale behind the analgesic property of cocaine (consider pKa and relate to moa)
for local anesthetics, important for pKa to allow for extent of ionisation such that there is no ionisation to favour permeability then ionisation to favour its activity
pKa of cocaine if 8.6, has an ionisable amine group thus it is a strong base
- pKa favours membrane permeation at physiological pH of 7.4
i) since pH < pKa approx 1u and cocaine is a base, cocaine will be 91% protonated
ii) cocaine should be unionised so that it is more lipophilic to facilitate passage across membrane
iii) then once in interior of nerve cells then pH 7.4, cocaine will undergo ionisation to form a cation which will be able to inhibit the Na channel bc it req a pos charge - pKa favours binding to Na channel
i) exerts its analgesic effect by binding to Na channel and blocking the influx of Na+ ions through the Na channel
what are the key chemical structures of cocaine for its analgesic property
- aromatic carboxylic acid ester
- basic amino group
- lipophilic hydrocarbon ring
*non polar (hydrophobic) structures can also help to make it conducive for penetration
what are the unwanted s/e of cocaine
allergic rxn, skin irritation, addiction, withdrawal, poor stability in aq solution
what SAR strategy was adopted for cocaine and what does this show (elaborate on the SAR changes to cocaine structure)
using dysjunctive (simplification) approach to retain therapeutic effect of cocaine but eliminate unwanted s/e
(shows that simplification method is not just useful for potency but also for addressing s/e)
- lipophilic portion (benzene or heterocycle)
i) essential bc facilitates permeation
ii) ensure the pKa of molecule (aka hydrophobicity) is ok for permeation and absorption) - intermediate chain (ester or amide; less commonly ether or keto f/b 1-3C chain)
i) chain determines chemical stability and influences the duration of action (eg. amide more resistant to hydrolysis thus would have longer duration of action) - hydrophilic portion (secondary or tertiary amine/ N heterocycle)
i) should be basic and ionisable to give cation bc pos charge req to interact w Na channel
ii) also helps facilitate formulation as an injectable
iii) extent of deprotonation from amine determines the ability of agent to permeate across membrane vs protonated form facilitates binding to Na channel
pKa of most local anesthetics range from 7.5-9
what are the structures derived from SAR of cocaine and elaborate on their respective properties
TROPACOCAINE (BENZOYLTROPINE)
i) removal of carboxymethoxy group at pos 2 of cocaine
ii) eliminated addiction liability
iii) found to have strong local anesthetic property (look under procaine)
BENZOCAINE
i) good anesthetic property and low toxicity
ii) but low water solubility
iii) LogP = 1.8, pKa = 2.8
iv) consists of alot of non polar and hydrophobic groups (benzene, ester with ethyl)
v) also has an ionisable amino group which is a weak base bc lone pair can delocalise into benzene thus not charged at all at a certain pH making it have low water solubility
PROCAINE
i) low systemic and local toxicity but short duration of action bc of tertiary amine bc it is able to be hydrolysed readily
ii) derived from the removal of tropine (heterocycle) from benzoyltropine (tropacocaine)
iii) benzoyl ester of amino alcohol showed strong local anesthetic property (i think this mean benzoyltropine has strong local anesthetic property)
how was lidocaine (lignocaine) derived and what are its properties
DERIVING LIDOCAINE
i) derived from isogramine
ii) through ring opening and insertion of amide to form lidocaine
PROPERTIES
1. better water solubility
i) amide quite polar thus enhances water solubility
- longer duration of action compared to procaine
i) amide is more resistant to hydrolysis (C=N formed due to resonance of amide which is stronger than C-O in ester)
ii) two methyl groups hinder approach of molecules - first amide type local anesthetic agent
- less allergenic
- more stable in water
- good anesthetic agent
how can anesthetics be classified
based on their func groups
- ester local anesthetics (amino ester)
i) cocaine
ii) procaine
iii) tetracaine
iv) 2-chloroprocaine - amide local anesthetics (amino amide)
i) lidocaine
ii) bupivacaine
iii) mepivacaine
iv) prilocaine
v) etidocaine
vi) ropivacaine
vii) levobupivacaine - amino ether anesthetic
i) promoxine - amino ketone anesthetic
i) dyclonine
*remember to always start by finding the three main portions of a local anesthetic (lipophilic, intermediate, hydrophilic) then determine the func groups it has!
draw out the general synthetic schemes for local anesthetics
i) draw one to form aminoester type of local anesthetic (one step)
ii) draw one to form aminoamide type of local anesthetic (two step)
involves nucleophilic substitution so a good leaving group is impt
what is the rationale behind pts having cross sensitivity to p-amino benzoic acid and procaine
cross sensitivity occurs after hydrolysis
why does procaine have a slow onset of action when tissue pH is 7
procaine has a pKa of 9
since pH < pKa by 2u, ionisation of a weak base is 99% thus it makes procaine less lipophilic and unable to permeate
why is procaine formulated as 1% or 2% strength while bupivacaine is formulated as 0.25% or 0.5%
procaine has a LogP of 1.9 while bupivacaine has a LogP of 4.5
bupivacaine is more lipophilic than procaine thus it is relatively more potent and thus unlikely to be formulated at higher conc
what are the properties of an ideal local anesthetic agent
i) produces a reversible blockade
ii) selectivity for sensory neurons with no effect on motor neurons
iii) rapid onset
iv) sufficient duration of action
v) chemically stable when sterilised
vi) no systemic toxicity
vii) wide margin of safety
viii) compatible with other co-administered drugs
ix) absence of adverse effects
x) inexpensive
where is opium derived from
derived from the flower of poppy plant (papaver somniferum) which produces a capsule which when ripened can be cut and exclude the milky latex
opium is the air dried milky latex
what structure do alkaloids from poppy plants have (draw structure and list eg. of drugs)
opium alkaloids include morphine, codeine, thebaine, papverine, noscapine, narceine
morphine’s structure was derived from benzyltetrahydroisoquinoline
morphine, codeine, thebaine have structures similar to morphinan
i) all three have added O, substituent on benzene at pos 3, OH at pos 6, and one or two double bonds in bottom hydrocarbon ring and CH3 substituent at pos 9a (N atom)
ii) morphine has added O, OH at pos 3, OH at pos 6, one double bond at 7-8, CH3 substituent to N at pos 9a
iii) codeine has added O, OCH3 at pos 3, OH at pos 6, one double bond at 7-8, CH3 substituent to N at pos 9a
iv) thebaine has added O, OCH3 at pos 3, OH at pos 6, two double bonds at 8-14 and 6-7, CH3 substituent to N at pos 9a
what are the properties of morphine
i) originate from benzyltetrahydroisoquinoline
ii) entire top of poppy plant harvested f/b dried and extracted (morphine extracted and purified)
iii) purified morphine can be used for synthesis of other medicines through SEMI-SYNTHESIS of codeine, dihydrocodeine, pholcodein, heroin
iv) is a powerful analgesic and a narcotic (very effective for severe pain)
v) but frequent usage also induces a state of euphoria and mental detachment, along with N/V/C, tolerance and addiction
vi) metabolised in the body at pos 3 and 6 to form morphine 3-O-glucoronide (antagonist to the analgesic effects of morphine) and morphine 6-O-glucoronide (more effective and longer lasting analgesic than morphine)
vii) morphine also led to production of other synthetic opioid drugs like pentazocine, pethidine, fentanyl, tramadol, remifentanil, alfentanil, methadone
what are the properties of codeine
i) 3-O-methyl ether of morphine (derived through semisynthesis from morphine via mono-O-methylation at the acidic phenolic hydroxy group using dimethyl sulfate)
ii) widely used analgesic with 1/10 the potency of morphine
iii) relatively safe and non addictive medium analgesic but is still too constipating for long term use
iv) almost always taken PO
v) also has valuable antitussive action, helping to relieve and prevent coughing by effectively depressing the cough centre and raising the threshold for sensory cough impulses
apart from codeine what other drugs can be derived from the semisynthesis of morphine (elaborate on each of their structures and their properties)
pholcodeine, dihydrocodeine, diamorphine (heroin)
PHOLCODEINE
i) effective and reliable antitussive
ii) obtained by alkylation of morphine with N-(chloroethyl)morpholine
DIHYDROCODEINE
i) reduced form of codeine with similar analgesic properties
ii) shows that double bond in codeine is not essential for activity
DIAMORPHINE (HEROIN)
i) diacetate of morphine (esterified product of morphine)
ii) highly addictive analgesic and hypnotic
iii) two hydroxyl groups react with acidic anhydride in presence of pyridine to give two esters at pos3 and pos6
iv) the incr lipophilic character results in better transport and absorption
what are the synthetic opioid drugs and their features (elaborate on structure and properties)
these synthetic opioid drugs are analogues of morphine: pentazocine, pethidine, fentanyl, alfentanil/ remifentanil, tramadol, methadone
PENTAZOCINE
i) O-bridge omitted
ii) replace cyclohexene with simple methyl groups (should have added two)
iii) good analgesic, no addiction, but have withdrawal sx
PETHIDINE
i) widely used synthetic opioid
ii) less potent than morphine but able to produce prompt short acting analgesia
iii) less constipating than morphine but can be addictive
iv) only aromatic ring (phenol) and piperidine system retained
FENTANYL
i) 4-anilino- rather than a 4-phenyl-piperidine structure (anilino is N with benzene ring)
ii) 50-100x more active than morphine due to higher lipophilicity and excellent transport properties
ALFENTANIL/ REMIFENTANIL
i) further variants of fentanyl structure
ii) all are rapid acting
iii) use during operative procedures
TRAMADOL
i) claimed to have analgesia like an opioid through enhancement of serotoninergic and adrenergic pathways with few typical opioid s/e
ii) simplified molecule containing 3-methyl-phenyl cyclohexane (OCH3 substituent on benzyl attached to cyclohexane)
METHADONE
i) piperidine ring no longer present
ii) contains diphenylpropylamine which can mimic piperidine ring conformation
iii) PO and similar activity to morphine but less euphorigenic and longer duration of action
iv) potentially as addictive as morphine
v) withdrawal sx different and much less severe than other drugs (like heroin)
vi) widely used for tx and rehabilitation of heroin addicts
apart from morphine and its semi synthetically produced agents, what are other opioids (elaborate on their structure and moa properties)
other opioids incl oxycodone, oxymorphone, naloxone, naltrexone, nalbuphine (from left to right: agonist to antagonist, except nalbuphine has mixed)
NALBUPHINE
i) produced semi synthetically from thebaine
ii) mixed agonist-antagonist properties
iii) similar agonist as morphine but less s/e and less abuse potential
NALOXONE
i) potent antagonist at all opioid receptors
ii) tx opiate poisoning (incl children born to heroin addicts)
iii) N-alkyl derivatives of oxycodone/ oxymorphone
NALTREXONE
i) similar antagonistic activity to naloxone
ii) N-alkyl derivatives of oxycodone/ oxymorphone
*between naloxone, naltrexone and nalbuphine, the difference is only in the substituent on N at pos 9a
*between oxycodone and oxymorphone, difference only at substituent to benzene ring at pos 3 (oxycodone is OCH3 while oxymorphone is OH
