Med Chem - Parkinsons Flashcards
dopamine and ACh levels in parkinsons
low dopamine
high acetylcholine
the cause of parkinsons is largely unknown
however, what 1 molecule has been actually linked to degeneration of dopaminergic neruons in the substantia nigra
MPTP
4 distinct clinical features of parkinsons
bradykinesia
tremors
rigidity
postural instability (later)
true or false
the incidence of parkinsons increases with age
true
in PD, there is a gradual destruction of ____
dopamine containing neurons
leads to dopamine deficiency
in PD, there is impaired ____ pathway which is crticial to coordinated movements
impaired nigro-striatal pathway
true or false
it is not possible for environmental changes to increase the risk for PD
false - it is
like exposure to herbicides
what is the biosynthetic precursor of dopamine
L-tyrosine
explain the biosynthesis of dopamine
precursor L-tyrosine
hydroxylation by tyrosine hydroxylase to L-DOPA
then decarboxylation by AAD (aromatic amino acid decarboxylase) to form DOPAMINE
which 2 enzymes metabolize dopamine
COMT and MAO-B
true or false
COMT inhibitors and MAO-B inhibitors increase dopamine levels
true
neurotoxicity results from the buildup of toxic byproducts of….
DOPAMINE METABOLISM
-electrophilic quinone and semiquinone (dopamine autooxidation - it’s a catechol so susceptible to oxidation)
-epoxide intermediate (from tyrosine to L-dopa)
-hydroxyl radical formed from hydrogen peroxide (by product of MAO-B metabolism)
in an autopsy of a PD patient:
___ levels of GSH
___ lipid peroxidation
____ oxidation of DNA and proteins
decreased GSH
increased lipid peroxidation
increased oxidation of DNA and proteins
name 4 dopamine receptor agonists that can be used for PD
pramipexole
ropinirole
rotigotine
apomorphine
name 3 MAO B inhibitors
selegiline
rasagiline
safinamide
carbidopa MOA
inhibits AAD ONLY IN THE PERIPHERY
thus prevents dopamine formation in the periphery
L-dopa crosses BBB through L-amino acid transporter – then AAD converts it to dopamine in the BRAIN
what is the cofactor in the AAD reaction
PLP
effect of high dose vitamin B6 being given with carbidopa-levodopa
reversed therapeutic effects
bc high dose vitamin B6 increases the peripheral AAD action – more dopamine will be formed in the periphery which the drug is trying to avoid
most L-dopa is converted to dopamine where
in the periphery
true or false
L-dopa is rapidly metabolized
TRUE
rapidly decarboxylated by 1st pass in the liver
2 principle metabolites of dopamine
HVA
DOPAC
can carbidopa cross the BBB? why??
NO - TOO POLAR
MOA carbidopa
inhibits AAD in the periphery by trapping the pyridoxal phosphate cofactor via schiff base interaction
can dopamine cross the BBB
NO - TOO POLAR. and doesnt mimic anything enough to use its transporter
true or false
levodopa is more polar than dopamine
TRUE
but levodopa is the one that can cross the BBB bc mimics tyrosine and phenylalanine - uses L-amino acid transporter
true or false
selegiline and rasagiline are selective, reversible MAO-B inhibitors
false - selective and irreversible
inhibiting MAO-B in the brain of PD patients lead to ______ oxidation of dopamine
reduced
thus increased levels of dopamine in the brain
also decreased levels of toxic products like the hydroxy radical
true or false
when MAO-B inhibitors are given with sinemet, the L-dopa dose has to be increased
FALSE
MAO-B inhibitors potentiate the actions of dopamine, so the L-dopa dose can actually be reduced
explain the chemistry of how MAO-B inhibitors inhibit the enzyme
propargyl group is oxidized to form a michael acceptor
this michael acceptor reacts with a michael donor (the N5 nitrogen of FAD cofactor) the cofactor is tied up irreversibly, so MAO-B can’t work to metabolize dopamine
COMT is a methyl transferase that uses _____ as a cofactor
SAM
TRUE OR FALSE
COMT inhibitors mainly inhibit COMT in the brain
FALSE - the periperhy
true or false
COMT is regioselective
TRUE
always methylates at the meta position
all of the COMT inhibitors are -____ derivatives and are fairly ____ (acidic or basic)
nitrocatechol
acidic
do dopamine receptor agonists have a longer or shorter duration than L-dopa
what does this mean
LONGER DURATION
so less likely to induce on/off effects and dyskinesia
what structural feature of dopamine agonists is critical
A BASIC AMINE
must also be positioned properly to mimic trans alpha rotamer - most active
why are anticholinergics used in PD
dopamine depletion leads to loss of M4 autoreceptors
this leads to increased ACH release – leading to tremors
anticholinergics restore the balance of dopamine and acetylcholine
