Med Chem - Alzheimers Flashcards
what is the leading cause of dementia
alzheimer’s disease
what are the 2 main pathologic hallmarks of alzheimers
amyloid plaques (abnormal clusters of B-amyloid protein)
appearance of neurofibrillary tangles (made of tau protein)
in alzheimer’s disease, there is ____ overactivation and ___ deficit
NMDA receptor overactivation
acetylcholine deficit
in AD, the neurofibrillary tangles accumulate interneuronally or intraneuronally
intra
in AD, the B-amyloid protein plaques accumulate within the neuron or out of the neuron
out of the neuron - extraneuronally
true or false
in AD, AB production outweighs AB clearance
true
*what are the 2 fates of the amyloid precursor protein
name the enzymes involved**
either forms plaques or doesnt
if doesnt form a plaque - was cut by a-secretase (ADAM 10)
if DOES form a plaque, is cut by B-secretase/BACE-1. once cut, y-secretase cuts as well in the middle of the membrane.
this forms an AB monomer. the precision by Y-secretese determines the length of this monomer. it is normally between 38-43 aa. 42aa has a HIGH TENDENCY TO FORM PLAQUES
explain how intracellular neurofibrillary tangles made of tau protein are formed in alzheimers disease
normally, tau protein is attached to microtubule inside the cell. this tau protein can either be phosphorylated or dephosphorylated
in AD, there is upregulation of kinases and downregulation of phosphatases. thus, the tau protein gets hyperphosphorylated and these taus aggregate and form a tangle
true or false
current therapies for AD focus on addressing the pathological causes (AB plaques and tau protein tangles)
FALSE - no therapies for that yet
therapies now just are focused on enhancing memory function
true or false
in AD, there is too much acetylcholine
FALSE - too little
excess glutamate can lead to….
cell death
primarily mediated by NMDA receptor - BAD
what are the 3 neurotransmittors most commonly affected by AD
serotonin
NE
acetycholine (most)
3 classes of drugs for AD that exist at the moment
ACHE inhibitors
nicotinic acetycholine receptor agonists
NMDA receptor antagonists
in AD, acetylcholine levels are low.
this is possibly due to a decrease in what 2 things
decrease in:
-choline transporters
-choline acetyltransferases
what is the major/minor pathway for ach synthesis
major - from recycled choline
minor - from serine
what is the biosynthetic precursor of acetylcholine
serine
what is the precursor of serotonin
tyrosine
what is the precursor of GABA
glutamate
*the catalytic triad of the esteratic site of ache is formed by what 3 amino acids
serine, histidine, and glutamate
*in the hydrolysis of acetylcholine by acetylcholine esterase, which amino acid gets acetylated and thus only choline is left behind
serine-200
explain how ACHE I work in alzheimers patients
prevent the breakdown of acetycholine, brain chemical believed to be important for memory and thinking
name 2 REVERSIBLE AchE inhibitors for AD
donepezil
galantamine
name a pseudoirreversible ACHE inhibitor
rivastigmine – has a carbamate
memantine MOA and how it’s helpful in AD patients
NMDA receptor antagonist
protects against the destructive effects of too much glutamate
true or false
the basic Nitrogen of donepezil must be at position 4
true
true or false
donepezil is peripherally acting
FALSE - central acting
needs to be centrally acting to be used for AD
true or false
donepezil is a reversible, competitive inhibitor of ACHE
false
reversible, noncompetitive
true or false
donepezil has similar selectivity for ACHE vs BUTECH
false – lot more selective for ACHE, and also more selective for ACHE in the brain rather than in the periphry
dual MOA of galantamine
ACHE inhibitor
acts at an allosteric nicotonic site to increase cholinergic action (nACHR agonism!)
memantine blocks glutamate-induced excitotoxicity
it does this by binding where exactly?
close to the magnesium binding site within the NMDA ion channel
true or false
memantine is a noncompetitive inhibitor
true
true or false
memantine binds with high affinity
FALSE - low affinity
this is good tho bc it has a better AE profile
