chemistry Flashcards
opium alkaloids
aka opiates
centrally acting analgesics
strong narcotic effect
indication of opioids
- moderate to severe pain
- cough
- diarrhoea
- opioid dependence
common adr of opioids
respiratory depression
nausea and vomiting
drowsiness
delta (opioid receptor) and its agonist function
analgesia
antidepressant
physical dependece
kappa and its agonist function
spinal analgesia
sedation
miosis
inhibition of ADH release
mu and its agonist function
u1- supraspinal analgesia
physical dependence
u2-respiratory depression
miosis and reduced GI motility
nociceptin receptor and agonist function
anxiety
depression
appetite
toelrance to mu agonist
body snatural antiiniceceptives
endorphins (EnDOgenous moRPHINES)
enkephalin
-smaller peptides
morphine structure
5 rings (A-E) T shape
functional modificaiton of the R groups on morphine to yield codeine, ethylmorphine and 3-acetylmorphine leadsw to what in terms of analgesic activity
decreased analgesic activity
how does codeine act as prodrug for morphine
codeien is converted to morphine in the liver
functional modification of the 5-OH led to what in terms of activity
4-5 fold increase
testing of analgesics
performed in vivo
many factors must be considered as to why activity increase
ultimate resistance of opioid analgeics to CNS
BBB
6-acetylmorphine and heroin highly lipophilic therefore can penetrate the lipophilic bilayer and enter CNS
more polar morphine cannot readily penetrate the BBB
how do we get dihydromiorphine
preapred by hydrogenation of morphine
double bond at c7-c8
activity is not comprimised therefore double bond not essential for activity
N methyl groups in morphine functional modification
n-oxide or n methyl quayernary salts are ianctive in vivo as they are charged molecules therefore cannot cross BBB
N methyl groups in morphine functional modification and interaction with the receptor
since molecules are permanent cationsn nitrogen must be charged wihen inteacting with the receptor
normorphine in terms of polarity and activity
increased polarity therefore decreased activity
normorphine and removal of notrigen atoms
leads to total abolition of activity
nitrogen atoms is essential for activity and interacts with the receptor in ionised form
aroamtic ring in morphine
essentials
removal leads to loss of activity
ether bridge in morphine
not required for analgesic activity
mehtly group in morphine
not essential for analgesic activity
sterochemistry of morphine
contains everal chiral centers
enantiomer is completely inactive
enantiomer of morphine and why its completely inactive
morphine forms 3 receptor interactions with the binding regions
enenatiomer has no alagesic activity as it only has 1 receptor interaction
eprimerixation of morphine and its effects
leads to drastic change in molecular shape
result in poor conformation for receptor bindsing
pharmacophore of morphine
3D positioning of the key function groups with respect to each other
orginal structure-skeletal pharmaocophore-pharmacophoric triangles
metabolic pathway of codine
morphine via o-demethylatuion
norcodeine (N-demethylation)
morphine metabolic pathway
N demethylaton-normorphine
ugt2b7- morphine -6-glucoronide (mroe active)
ugt2b7, paps-morphine 3 glucorodine or sulfate (inactive)
which metaboltie of morphine is more reactiube than itself
morphine 6 glucoronide
phase 1 reaction of morphine
many mu receptor agonists have an N methyl group which is readily dealkylated by CYP3A4
nor metabolite from dealkylation
nor-lacking a methyl group
why nor metabolites have limited clincial relevance
dicreas ein distribution enhancing lipophilicity
loss of agonist promoting hydrophobic interaction witht he receptor
patients deficient in cyp2D6
unable to 0-dealkylate codeine and therfore show little or no response to codeine based analgesic
common metabolic reactions phase 2
phenols conjugate with either glucoroic acid
what impacts oral bioavailability of many phenolic opioids
phase 2 conjugation in the GI tract
morphine 6 glucoronide and morphine. potency
estimated to be 50:1
in whom can m6G accumulate in
although readily excreted it can accumulate in patients with renal failure or poor renal function
varying substittuents to develop morphine monologues
a series of phenolic alkylation products led to a group of poor or inactive compounds
extending molecular structure in developemt of morphine analogues
drug extension is a strategy in which the molecule is extended by addition of potential extra binding groups
easiest position to add substituent uto is the nitrogen atoms
-N demethylation required
in N alkylmorphines. activity of the structure if the R2 is ch2ch2Ph (phenethyl)
14x activity of morphine
in N alkylmorphines activity of the structure if the R2 is pentanyl, hexanyl
agonists
in N alkymorphines activity of the strucutre if the R2 is Bu
zero activity
in N alkylmorphines activity of the strucure if the R2 is me, Et, Pr
agonism decreases
antyagonism increases
allyl and cyclopropylmethyl
when these groups were attached yield astounduing resutls
poses no analgesic activity therefore used to tx of opiates overdose
agonists and the equilibrium between active conformation and inactive conformation
switches the equilibrium in favour for the active confromation which increases signal transduction
antagonsits and the equlibrium between active and inactive conformation
switches the equilibrium in favour of the inactive conformation which leads to a decreased signal transduction
amount of rings in morphine
5
loss of ring E
complete loss of activity
loss of ring d
removal of cyclic ether
formation of morphinans
n-methylmorphinans
20% analgeisc activity
levorphanol
5x more potent that morphine
removal of rings c and d
benzomorphans
retain analgesic activity
removal of b c and rings
4-phenylpiperidines
fentanyl
successful piperidicine deivatibe
100x more potent that morphione
what does fentanalyl strucutre lack
phenolic-oh
extrememly lipophilic
removal of b c d e ring
methadone
methadone in terms of severity of side effects
dispalays less servere emesis, constipation, sedation, euphoria
r isomer of methadones activity
responsible for the analgesic activity
s isomer of methadones activity
anatagonises the nmda receptor
where is methadone beneficial in
neuropathic and opioid resistant pain
why does methadone have a prolonged duration of action
generation of serveral active n-dealkylated and c3 redyuced metabolites
some metabolites also have long t0.5
administration of methandone
oral
injection
methandone and its risk of fatal cardiac arrhythmias
prlonged qt interval
tramadol
analgesic with multiple moa
weak mu agonist
pateitns allergic to cordine should not recieve tramadol why
risk for anaphylatic shock
tramadol and enantiomer differences
1r, 2r enantiomer 30x more potent than 1s,2s enantiomer
tramadol and its metabolsm which is similar to codeine
o-demethylate via cyp2d6 to a mroe potent opioiid rceptor agonist
diels alder reaction
cycloaddition reaction between diene and dienophile to form a six membrered ring containing a double bond
formation of oripavines
using methyl vinyl ketones as the dienophile intriduces reactive ketone group into molecule
etorphine
1000x mroe ptoent than morphine
used as tranquilizers for large animals
bupernorphine
drug extension led to this
good analgeisc activity
