Med Chem - Parkinsons

Question 1

dopamine and ACh levels in parkinsons

Answer 1

low dopamine
high acetylcholine

Question 2

the cause of parkinsons is largely unknown

however, what 1 molecule has been actually linked to degeneration of dopaminergic neruons in the substantia nigra

Answer 2

MPTP

Question 3

4 distinct clinical features of parkinsons

Answer 3

bradykinesia
tremors
rigidity
postural instability (later)

Question 4

true or false

the incidence of parkinsons increases with age

Answer 4

true

Question 5

in PD, there is a gradual destruction of ____

Answer 5

dopamine containing neurons

leads to dopamine deficiency

Question 6

in PD, there is impaired ____ pathway which is crticial to coordinated movements

Answer 6

impaired nigro-striatal pathway

Question 7

true or false

it is not possible for environmental changes to increase the risk for PD

Answer 7

false - it is

like exposure to herbicides

Question 8

what is the biosynthetic precursor of dopamine

Answer 8

L-tyrosine

Question 9

explain the biosynthesis of dopamine

Answer 9

precursor L-tyrosine

hydroxylation by tyrosine hydroxylase to L-DOPA

then decarboxylation by AAD (aromatic amino acid decarboxylase) to form DOPAMINE

Question 10

which 2 enzymes metabolize dopamine

Answer 10

COMT and MAO-B

Question 11

true or false

COMT inhibitors and MAO-B inhibitors increase dopamine levels

Answer 11

true

Question 12

neurotoxicity results from the buildup of toxic byproducts of….

Answer 12

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)

Question 13

in an autopsy of a PD patient:

___ levels of GSH
___ lipid peroxidation
____ oxidation of DNA and proteins

Answer 13

decreased GSH

increased lipid peroxidation

increased oxidation of DNA and proteins

Question 14

name 4 dopamine receptor agonists that can be used for PD

Answer 14

pramipexole
ropinirole
rotigotine
apomorphine

Question 15

name 3 MAO B inhibitors

Answer 15

selegiline
rasagiline
safinamide

Question 16

carbidopa MOA

Answer 16

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

Question 17

what is the cofactor in the AAD reaction

Answer 17

PLP

Question 18

effect of high dose vitamin B6 being given with carbidopa-levodopa

Answer 18

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

Question 19

most L-dopa is converted to dopamine where

Answer 19

in the periphery

Question 20

true or false

L-dopa is rapidly metabolized

Answer 20

TRUE

rapidly decarboxylated by 1st pass in the liver

Question 21

2 principle metabolites of dopamine

Answer 21

HVA
DOPAC

Question 22

can carbidopa cross the BBB? why??

Answer 22

NO - TOO POLAR

Question 23

MOA carbidopa

Answer 23

inhibits AAD in the periphery by trapping the pyridoxal phosphate cofactor via schiff base interaction

Question 24

can dopamine cross the BBB

Answer 24

NO - TOO POLAR. and doesnt mimic anything enough to use its transporter

Question 25

true or false levodopa is more polar than dopamine

Answer 25

TRUE but levodopa is the one that can cross the BBB bc mimics tyrosine and phenylalanine - uses L-amino acid transporter

Question 26

true or false selegiline and rasagiline are selective, reversible MAO-B inhibitors

Answer 26

false - selective and irreversible

Question 27

inhibiting MAO-B in the brain of PD patients lead to ______ oxidation of dopamine

Answer 27

reduced thus increased levels of dopamine in the brain also decreased levels of toxic products like the hydroxy radical

Question 28

true or false when MAO-B inhibitors are given with sinemet, the L-dopa dose has to be increased

Answer 28

FALSE MAO-B inhibitors potentiate the actions of dopamine, so the L-dopa dose can actually be reduced

Question 29

explain the chemistry of how MAO-B inhibitors inhibit the enzyme

Answer 29

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

Question 30

COMT is a methyl transferase that uses _____ as a cofactor

Answer 30

SAM

Question 31

TRUE OR FALSE COMT inhibitors mainly inhibit COMT in the brain

Answer 31

FALSE - the periperhy

Question 32

true or false COMT is regioselective

Answer 32

TRUE always methylates at the meta position

Question 33

all of the COMT inhibitors are -____ derivatives and are fairly ____ (acidic or basic)

Answer 33

nitrocatechol acidic

Question 34

do dopamine receptor agonists have a longer or shorter duration than L-dopa what does this mean

Answer 34

LONGER DURATION so less likely to induce on/off effects and dyskinesia

Question 35

what structural feature of dopamine agonists is critical

Answer 35

A BASIC AMINE must also be positioned properly to mimic trans alpha rotamer - most active

Question 36

why are anticholinergics used in PD

Answer 36

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