Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

811 > Lecture 32/33 > Flashcards

Lecture 32/33 Flashcards

Anticholinoesterases - Feng

1
Q

AChEI

A
  • Indirect acting cholinomimetics

- Increase ACh by decreasing AChE hydrolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

AChE + Hydrolysis

A
  • ACh = ester
  • ACh signaling is terminated by catalytic ester hydrolysis by AChE
  • AChE cleaves 10,000 ACh per second, VERY efficient, reaching almost diffusion reaction rates
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Electrophiles + Nucleophiles

A
  • Electrophiles love electrons (electron deficient)
  • Cleavage of esters from nucleophilic attack
  • Nucleophile has lone pair of electrons that donate and form new bond to electrophile
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Acid-Catalyzed Hydrolysis

A
  • Ester reversibly goes between being a weak and strong electrophile by transferring partial charges
  • Hydrolysis in increased by the transforming into a strong electrophile which activates the carbonyl carbon
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Base-Catalyzed Hydrolysis

A

-Accelerated by a strong nucleophile like -OH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Catalytic Triad - AChE

A
  • serine hydrolase has triad: Glu-His-Ser
  • Serine acts as the nucleophile
  • Histadine residue increases the nucleophilicity by removing proton from serine
  • Glutamate interacts with imidazole to orient
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Hydrolysis Steps

A
  1. Nucleophilic attack of carbonyl carbon by deprotonated serine (base-catalyzed), acetylated AChE = inactive
  2. Regeneration - assisted by histadine group (acid-catalyzed), crucial step for AChEI, when acetylated with carbamyl or phosphate the enzyme is more stable when inactive and hydrolysis take a lot longer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

AChE + Acid/Base Catalysis

A
  • Base-catalyzed hydrolysis portion: -OH from serine in nucleophilic attack
  • Acid-catalyzed hydrolysis portion - imidazole proton protonating carbonyl O
  • Makes this enzyme super efficient with fast rates by utilized both aspects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Ester AChE Inhibitors

A
  • Classic
  • Carbamates or phosphoesters
  • Compete for site of activation
  • Close in structural and chemical properties to ACh
  • Inhibits AChE so that ACh can’t bind and it returns to the receptor to activate it
  • Same effect as cholinergic agonist
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Reversible Inhibitor Types

A
  1. Substrates that slow hydrolytic regeneration (carbamates)

2. Binds with AChE with greater affinity but does NOT react as substrate (edrophonium)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Carbamyl Inhibitors

A
  • Esters of carbamic acid
  • Interacts with AChE as a substrate but increases the time to regenerate enzyme (Ex: insecticide)
  • Minutes to regenerate, but the enzyme will work again (reversible)
  • Form covalent bond with Serine-O
  • Slower regeneration rate since carbonyl C of carbamate is less electrophilic than acetate (water is less attracted to it)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Electronic Factors

A

-Carbonyl groups are stabilized by delocalizing nitrogen lone pair onto the carbonyl

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Aryl Carbamate

A
  • Better than alkyl since aryl is a better leaving group
  • Phenoxide anion drives reaction to completion with serine
  • Therefore, carbamylates AChE quickly to inhibit it
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Physostigmine: SAR

A

-Tertiary amine
-Natural product from African calabar bean
-Activity varies based on pH (more activity at lower pH), contributes that the positive charge is important for activity
1. Carbamate = essential (equiv. to ester)
2 Aromatic ring = important (good leaving group)
3. Pyrrolidine N = important, ionized in blood, equiv. to quart. N of ACh

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Physostigmine Analogs

A
  1. Miotine

2. Neostigmine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Miotine

A
  • Simplified analog of Physostigmine
  • Susceptible to hydrolysis
  • Crosses BBB as free base
  • CNS effects
17
Q

Neostigmine

A
  • Fully ionized
  • Doesn’t cross BBB
  • No CNS effects
  • Constant inhibition activity regardless of pH
  • More stable to hydrolysis by adding extra N-Me group
  • Carbamylates AChE
18
Q

Neostigmine SARs

A
  1. Carbamate with extra N-Me
  2. Benzene ring
  3. Quart. Ammonium
19
Q

Edrophonium

A
  • Short acting inhibitor that binds to ionic site but NOT esterase site of AChE
  • simple alcohol with quart. ammonium group, binds electrostatically by hydrogen bonds
  • Edrophonium doesn’t make covalent bonds with AChE
  • Enzyme inhibiting complex is short lived and therefore short acting
20
Q

Alzheimer’s + AChEI

A

-Important because there is decreased activity of chol. neurons, therefore increasing ACh level in brain
-This combats the loss of ACh in brain from death of chol. neurons
EX: Rivastigmine (Exelon) - carbamate-derived AChEI, analog of Physostigmine
Donepezil (Aricept) - untypical AChEI that reacts with active and peripheral site

21
Q

Non-Classic AChEI

A

-Binds to AChE with higher affinity than ACh but doesn’t react with enzyme as substrate
EX: Tacrine and Velnacrine

22
Q

Tacrine

A
  • Approved by FDA for Alzheimer’s
  • D/C in 2013
  • Tertiary amines
  • Well absorbed
  • Used systemically
  • Will cross BBB and enter CNS
23
Q

Irreversible AChEI

A
  • Phosphoesters - pesticides
  • Organo-phosphates undergo initial binding and hydrolysis by the enzyme, resulting in phosphorylated active site
  • Covalent phosphorous-enzyme bonds are VERY stable and therefore VERY slow to hydrolyze (hours)
  • Much longer duration of action which is considered “irreversible” since new enzyme synthesis if required to recover enzyme function
24
Q

Aging of AChEI + ChE Reaction

A
  • Aging is from dealkylation from partial hydrolysis of phosphate =O to -OH
  • Results are poor electrophiles
  • These poor electrophiles don’t allow for hydrolysis to activate or reaction with antidote to occur
  • Phosphorous atom of anionic P is less electrophilic
  • Explains why these were used for insecticides and in chemical warfare (their use here pushed for the research of antidotes)
25
Q

Warfare Use of Organo-Phosphorous Compounds

A
  • Deadly agent in warfare (Iraq 1980-88) and terrorism (Tokyo Subway Attack 1995)
  • Agent irreversibly inhibits AChE, “permanent” activation of chol. receptors by agent which leads to asphyxia due to inability to control pulmonary and diaphragm muscles which causes death
  • AChE disabled for hours to days
26
Q

DIFD

A
  • Agent used in warfare
  • Irreversible phosphorylation
  • F = good leaving group
  • Aging process occurs
  • P-O bond is very stable (Ser-O-P)
27
Q

Organo-Phosphorous Antidote

A
  • Needs to cleave P-O bond
  • AChE disabled, regeneration via antidote only occurs BEFORE aging
  • Aged AChE is permanently disabled
28
Q

Antidote Design

A
  • Strong nucleophile is required to cleave P-O bond
  • Needs to be suitable to cleave phosphate esters
  • Water is too weak
  • Hydroxylamine is a stronger nucleophile but is too toxic for clinical use
  • Therefore, need to increase its selectivity by increasing its binding interactions
29
Q

PAM

A
  • Pyridine Aldoxime Methiodide
  • Oxime = chemical compound belonging to imines
  • When R1 = organix side chain and R2 = H, then its an oxime
  • Quat. N is added to bind to anionic region of receptor
  • Side chain designed to place hydroxylamine moiety in correct position relative to P-Serine bond
  • Pralidoxime is a million times more effective than hydroxylamine
30
Q

PAM Nuc- Site

A
  • Oximes = used to reactivate phosphorylated AChE
  • 2-PAM has nucleophilic site (N-OH) that interacts with phosphorylated site on AChE
  • High degree of selectivity and strong binding affinity for AChE (due to positive charge) and carrier hydroxylamine-like nucleophile close to P-Serine
31
Q

PAM Mechanism

A
  • Oxime nucleophilically attacks the phosphorous atom
  • Frees serine from phosphate group
  • 1st line of defense against nerve gas since it reactivates ACh
32
Q

Limits of Pralidoxime

A
  • Only available agent to be determined as clinically effective as antidote for phosphate ester AChE poisoning
  • Can inhibit AChE at doses higher than optimal dose
  • Quat. ammonium can’t cross BBB
  • Aging decreases 2-PAM and other oxime reactivators’ effectiveness
33
Q

ProPAM

A
  • Prodrug of 2-PAM
  • Passes BBB as free base
  • Oxidized in CNS to 2-PAM by riboflavin
  • Then reactivated phosphorylated AChE in CNS
34
Q

Medicinal Organophosphates

A
  • Phospholine Iodide - used for glaucoma
  • Quat. N added to increase binding (more selective, lower doses, safer)
  • Utilizes similar concept to PAM
35
Q

Additional Functional Groups

A
  • Added on in components of nerve gas and medications
  • Adding Quat. N adds extra ionic binding
  • Stronger binding to AChE
  • Insecticides like this are toxic and must be handled with extreme caution
36
Q

Parathion –> Paraoxon (Insecticides)

A
  1. Thiophosphate insecticides are lipid soluble and rapidly absorbed
  2. Compounds have little AChEI activity since P -> S isn’t as nucleophilic as P -> O
  3. Rapidly bioactivated by desulfization by microsomal oxidation in insects to afford oxo derivatives to phosphate esters that are more potent
    - Insects have more oxidizing enzymes (like P450s) than we do
37
Q

Parathion in Mammals

A
  • Low AChEI activity
  • Metabolized into an inactive metabolite and is excreted
  • Poor detoxified though due to lack of carboxylate ester, therefore still dangerous to humans
38
Q

Malathion –> Malaoxon

A
  • Detoxified in birds and humans
  • Less toxic overall as insecticide
  • Carboxylate ester bond is the site of detoxification
  • Metabolized to a less toxic carboxylic acid metabolite which is rapidly excreted in urine as carboxylate anions in humans
  • Lower esterase activity in insects, leading to their death
39
Q

Aging + Malathion

A
  • With at least one phosphoester group, aging occurs in insects
  • Doesn’t happen in birds and humans since it is rapidly metabolized at carboxylate ester site
  • Two ester types in malathion: phosphoester and carboxylate ester

811 (38 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions