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PDAT5 CV > 2/3 - CHEMISTRY OF THE CHOLINERGIC NERVOUS SYSTEM > Flashcards

2/3 - CHEMISTRY OF THE CHOLINERGIC NERVOUS SYSTEM Flashcards

1
Q

NVP

A

Target:
Biostynthesis of Acetylcholine

Lead compound for
Inhibiting ChAT
Imitates Acetyl-CoA –> blocks Choline AcetylTransferase

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2
Q

Hemicholinium-3
HC-3

A

Target:

  • *Uptake of Choline**
  • *rate limiting step** in NT production

Competitive Uptake Inhibitor
does not get acetylated in PRE-synaptic cholinergic nerve terminals
Binds to 2 active carrier molecules
@ same time

HC3 blocks carrier protein A
but CANNOT enter the cell

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3
Q

TriethylCholine
TEC

A

False Neurotransmitter

Target:
Competes with CHOLINE for:
binding to the Uptake Carrier A / ChAT

Competing for acetylation to give TE-ACh
TE-ACh competes for vesicular ACh uptake in storage site
but it does NOT bind to cholinergic receptors
due to BULK

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4
Q

L-Vesamicol

A

Inhibitor of Vesicular ACh Uptake

non-competitive inhibitor
Binds to allosteric site –> prevents ACh binding

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5
Q

Drugs that target:
Release of ACh

A

Tetracycline
Complex Binding with Calcium

Botulinum Toxin
Blocks the release –> inhibits release of ACh from NM junctions
Cleaves SNAP-25

Beta-Bungarotoxin
PROMOTES the release –> exhaustion of ACh

Choline Alfoscerate - Alpha-GPC
INCREASE ACh concentration –> w/o exausting the supply

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6
Q

Tetracycline

A

Target:
Release of ACh
Complex Binding with CALCIUM
Ca2+ induces vesicles to fuse w/ the membrane

  • *Tetracycline** –> binds the free calcium
  • *↓Ca2+ concentration**
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7
Q

Botulinum Toxin

A

Target:
BLOCKS Release of ACh
from NM junctions

Cleaves SNAP-25
protein essential for docking & release of ACh from vesicles

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8
Q

Beta-Bungarotoxin

A

Target:
PROMOTE the release of ACh
VVV
EXHAUSTION of ACh
stores in the nerve terminal

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9
Q

Choline Alfoscerate
Alpha-GPC

A

Target:
Release of ACh

↑ACh Concentration
w/o exhausting ACh stores, like Beta-Bungarotoxin

Acetylation by LIPASES in the INTESTINE
–> LECITHIN = PhosphotidylCholine
can penetrate BBB due to LIPID SOLUBILITY

After entering brain –> hydrolyzed into CHOLINE

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10
Q

How does Choline Alfoscerate enter the BRAIN?
(Alpha-GPC)

↑ACh Concentration

A

Choline Alfoscerate is
ACYLATED by LIPASES in the INTESTINES
to make:
PhosphotidylCholine** = **Lecithin
which can:
penetrate BBB due to LIPID-solubility

After entering brain = hydrolyzed to choline

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11
Q

Muscarinic Antagonists
AKA - Antichoinergics

A

Naturally Occuring Tropine Alkaloids:
Atropine + Scopolamine
from
Deadly Nightshade = Belladonna

Synthetic Derivitives
Homatropine + Tropicamide

Quaternized = Do NOT cross BBB
Methscopolamine / Ipratropium / Tiotropium

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12
Q

Where are there

ONLY NICOTINIC RECEPTORS?

A
  • *NEUROMUSCULAR**
  • *ACh Receptors**

ACh Receptors of the:
CNS & Autonomic System have Both Muscarinic & Nicotonic

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13
Q

What type of receptor are

NICOTINIC RECEPTORS?

A

ION GATED CHANNELS
VVV
Change in Ion Concentration

AcetylCholine = Neurotransmitter
for BOTH Muscarinic & Nicotinic

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14
Q

What type of receptor are

MUSCARINIC RECEPTORS?

A

GPCR
7-Transmembrane helical structure w/​a-b-y subunits
VVV
Cascade of Chemical Reactions

AcetylCholine = Neurotransmitter
for BOTH Muscarinic & Nicotinic

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15
Q

How do Nicotinic Cholinergic Receptors work?

A

Normal Agonist = Nicotine/ACh
Sulfa Channels = CLOSED
ACh –> channel, Calcium Ion LEAVES
Free Sulfate group –> CONFORMATIONAL CHANGE on SULFATE BRIDGES
Opening of Ion Channels

Antagonism = Neurotoxin (Alpha-Bungarotoxin)

  • *Antagonist –> replaces CALCIUM
  • IRREVERSIBLE INHIBITION*** = channels STAY closed
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16
Q

How do MUSCARINIC RECEPTORS work?

Stimulation vs Inhibitory

A

STIMULATION
M1 / M3 / M5 (ODDS)
Lead to PLC –> CALCIUM RELEASE

  • INHIBITORY*
  • *M1 / M4**
  • *AC** –> _↓​cAMP RELEASE_
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17
Q

Modifications to Acetylcholine for Cholinergic Agonists:
What conformation of ACh is PREFERRED?

A

+TRANS +AC​
5x more potent when CONFORMATIONALLY RESRTRICTED
compared to flexible ACh

cis = inactive

-ac / trans = 1/50

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18
Q

Modifications to Acetylcholine for Cholinergic Agonists:

  • *Quaternary Ammonium Group**
  • *What improves binding / activity?**
A

+Positively Charged functional group
important for binding to receptors

2+ Methyl groups
on the charged functional group, is essential for agonist activity

Bottom is inactive due to steric hinderence

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19
Q

Modifications to Acetylcholine for Cholinergic Agonists:

  • *ACETYL**
  • *What improves binding / activity?**
A

Acetyl** –> **CARBOMYL

ORALLY ACTIVE

Carbomyl is:

  • less electrophilic* & more stable to hydrolysis
  • less readily hydrolyzed by GASTRIC acid*

(CH3 –> NH2)

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20
Q

Modifications to Acetylcholine for Cholinergic Agonists:

  • *ETHYLENE BRIDGE**
  • *What improves binding / activity?**
A

BETA-METHYL SUBSTITUTION
Muscarinic Agonist
B-M

  • *a-methyl substitution**
  • *Nicotinic Agonist**

double methyl sub = INACTIVE

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21
Q

Drug & Class?

A

CARBACHOL

no a/b substitution = both nicotinic & muscarinic agonist

Acetyl (of ACh) –> CARBOMYL = ORAL ACTIVITY

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22
Q

Drug & Class?

A

BETHANECHOL
treatment of urinary retention & ab distention

B-substitution = Muscarinic Agonist

Acetyl (of ACh) –> CARBOMYL = ORAL ACTIVITY

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23
Q

What Drug & Class?

A
  • *ATROPINE**
  • *Naturally occuring TROPINE alkaloid**
  • similar to ACh but bind better*

Muscarinic Antagonist = Anticholinergic = AntiMuscarinic

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24
Q

What Drug & Class?

A

SCOPOLAMINE

  • *Naturally occuring TROPINE alkaloid**
  • similar to ACh but bind better*

Muscarinic Antagonist = Anticholinergic = AntiMuscarinic

(3 x atropine, also a racemate)

25
Q

Cholinergic Blocking Agent = AntiMuscarinic

Requirements / Optimal Binding
@
R1

A

R1 = AROMATIC RING
essential for binding, VDW w/ receptor

POINTED BACKWARDS

The Ring can NOT tolerate anything other than:
F @ Para Position
without losing ANTAGONISTIC ACTIVITY

26
Q

Cholinergic Blocking Agent = AntiMuscarinic

Requirements / Optimal Binding
@
R2

A

R2 = Hydrophobic or Aromatic Ring (cycloalkyl)
Most potent = hydrophobic

size LIMITED

27
Q

Cholinergic Blocking Agent = AntiMuscarinic

Requirements / Optimal Binding
@
R3

A

R3 = H / OH / Carboxamide / HydroxyMethyl
for
HYDROGEN BONDING

can NOT tolerate BULK

28
Q

Cholinergic Blocking Agent = AntiMuscarinic

Requirements / Optimal Binding
@
X

A

X = Ester / Ester / Hydrocarbon

29
Q

Homatropine & Tropicamide

Type / Special fxn

A

AntiMuscarinics
w/

SHORTER Duration of Action vs Atropine

30
Q

MethScopolamine / Ipratropium / Tiotropium

Type / Special fxn

A

QUATERNIZED AntiMuscarinics
Quaternized = N+

that
do NOT cross the BBB

31
Q

Pirenzepine / Darifenacin / Solifenacin

Type / Special

A

Muscarinic antagonist
w/
RECEPTOR SELECTIVITY

Pirenzepine = M1

Darifenacin & Solifenacin = M3

32
Q

What Drug & Type?

A

PAROXETINE
antidepressant with high affinity to Muscarinic Receptors (mAChRs)

  • *R1** = Phenyl w/ FLUOURINE @ PARA position
  • still tolerable –> has AC EFFECTS*
33
Q

What drug & type?

A
  • *VENLAFAXINE**
  • *antidepressant WITHOUT AC side effects**
  • *R1 = Phenyl ring with -OCH3**
  • muscarinic receptor can’t tolerate anything more than a F@para*
  • loses its AC activity*
34
Q

AntiMuscarinic Agents with

AC Side Effects

A

Still have AC effects

Oxypenomium

Glycopyrrolate

Clidnium Bromide

Homatropine Methyl Bromide

35
Q

AntiMuscarinic Agents for

PARKINSON’S DISEASE

A

Parkinson’s disease = ↓Dopamine–>Chemical Imbalance
Tremor + Rigid Muscles

AC drugs –> ↓ACh

Dopamine levels closer to ACh levels = BALANCE

Trihexylphenidyl

Orphenadrine

Benztropine

Biperiden

36
Q

Drugs with
POTENT AC SIDE EFFECTS

A

Amitryptiline

Diphenhydramine

Clozapine

Disopyramide

37
Q

Drug Type?

Hexamethonium / Tetraethylammonium

A
  • *COMPETITIVE Nicotinic ANTAGONIST**
  • *Ganglionic Receptor Blockers**

Hexamethonium + Tetrathylammonium

38
Q

Drug Type?

A
  • NON-COMPETITIVE*
  • *Nicotinic ANTAGONIST**

Ganglionic Receptor Blockers

Trimethaphan Camsilate = SHORT ACTING
used for neurosurgical procedures which have excessive bleeding

39
Q
  • *Drug Type?**
  • *DECamethonium** (C10)

10-12 unsubstituted methylene groups

Hexamethonium C6 = ganglionic blocker

A
  • *Depolarizing NM Blockers**
  • *Nicotinic Antagonist**

SuccinylCholine - Decamethonium (C10)
10-12 unsub methylene groups

Bind tightly to ACh binding site on the nAChRs
–> over-stimulate the receptor

40
Q

Drug Type?

d-Tubocurarine / Gallamine / Pancuronium

A
  • *COMPETITIVE NM Blockers**
  • *Nicotinic Antagonist**

NM junctions are LARGE & don’t have a barrier/sheath
–> accessible to POLARized compounds

Used in:
ANESTHESIA

Bind but NOT tightly enough for antagonistic effect

41
Q
  • *MoA of
  • IRREVERSIBLE***AcetylCholineEsterase (AChE) Inhibitors

OrganoPhosphates
Drugs = Diisopropyl Fluorophosphate & Echotiopate
Chemical Warfare = Tabun / Sarin / Paraoxon
Insecticides = Thiophosphates = Parathion / Malathion

A
  • Inhibition of AChE*
  • *ACh** –/–> Choline + Acetic Acid = ↑ACh in Synaptic Cleft

PHOSPHRYLATED ENZYME INTERMEDIATE
Hours-Days = “Aging”

42
Q

MoA of
REVERSIBLEAcetylCholineEsterase (AChE) Inhibitors

Carbaryl
Physostigmine / Neostigmine
Pyrostigmine / Rivastigmine

A
  • Inhibition of AChE*
  • *ACh** –/–> Choline + Acetic Acid = ↑ACh in Synaptic Cleft

CARBAMOYLATED ENZYME INTERMEDIATE
15-20 min regeneration = Slow

43
Q

Reversible AChE Inhibitors

Drugs + Features

A

ARYL CARBAMATES
form carbamoylated enzyme intermediates = reversible AChE Inhibitors

Aromatic Ring + Carbamate

Carbaryl
-STIGMINE’s
Neostigmine / Pyridostigmine / Physostigmine / Rivastigmine

Aryl Carbamates > more efficient > ALKYL carbamates

44
Q

Drug Type / Features

A

PhysoStigmine = REVERSIBLE AChE Inhibitor
Carbamate Ester-Type

Lead compound = alkoloid from calabar bean

Glaucoma Treatment
&
Treatment for OVERDOSES of Compounds w/ ANTICHOL

CNS Effects = Atropine / TCA

45
Q

Drug Type / Features

A

Neostigmine = REVERSIBLE AChE Inhibitor
Carbamate Ester-Type

LACKS CENTRAL ACTIVITY
due to ionization

Uses:
Prophylaxis of POST-OP AB DISTENTION

Urinary Retention / Myasthenia Gravis

46
Q

Drug Type / Features

A

Pyridostigmine = REVERSIBLE AChE Inhibitor
Carbamate Ester-Type

LACKS CENTRAL ACTIVITY
due to ionization

Uses:
Longer duration of action + ORAL

Prophylaxis of NERVE GAS exposure

Myasthenia Gravis

47
Q

Which Carbamate Ester-Type

REVERSIBLE AChE Inhibitors

  • LACK CENTRAL ACTIVITY*
  • &*
  • *WHY??**
A

NEOSTIGMINE** + **PYROSTIGMINE

  • no central activity due to:*
  • *IONIZATION** = Has Charge –> can’t enter BBBAttach Images
48
Q

Drug Type / Features

A

RIVASTIGMINE = REVERSIBLE AChE Inhibitor
Carbamate Ester-Type

  • PSEUDO-Irreversible*
  • *<10 hours** –> slow dissociation of carbamylated enzyme

Centrally Acting –> Alzheimers Disease

49
Q

MoA of
_*IRREVERSIBLE* AChE Inhibitors_

A
  • *AGING PROCESS**
  • H2O** –> R2O Side = Aging –> *_IRREVERSIBLE_
  • Strengthened BOND = can NOT be hydrolyzed*

If added to the other side,
Hydrolysis

50
Q
  • SAR** of *_IRREVERSIBLE_ AChE Inhibitors
  • *ORGANOPHOSPHATES**

“A”

A
  • *A = Sulfa** –> PRODRUG
  • requires BIOLOGICAL ACTIVATION* before becoming an effective AChE inhibitor

A = O** –> **Active Drug

51
Q
  • SAR** of *_IRREVERSIBLE_ AChE Inhibitors
  • *ORGANOPHOSPHATES**

“X”

A

X = GOOD LEAVING GROUP

-F / -CN

-ThioMalate

-P-NitroPhenyl

52
Q
  • SAR** of *_IRREVERSIBLE_ AChE Inhibitors
  • *ORGANOPHOSPHATES**

R1

A

R1 = ALKOXYL

-ORR

53
Q
  • SAR** of *_IRREVERSIBLE_ AChE Inhibitors
  • *ORGANOPHOSPHATES**

R2

A

R2 = Alkoxyl / Alkyl / 3*Amine

-ORR

-RR

-NR3

54
Q

Drug Type / Uses?

A
  • *IRREVERSIBLE AChE Inhibitors**
  • *OrganoPhosphates**

Diisopropyl Fluorophosphate

EchoThiopate
used for local glaucoma treatment –> ~4 weeks

55
Q

Drug Type / Uses?

A

Tabun / Sarin / Paraoxon

  • *IRREVERSIBLE AChE Inhibitors**
  • *OrganoPhosphates**

GASES & CHEMICAL WARFARE AGENTS

Phosphateesters are very STABLE to hydrolysis

56
Q

Drug Type / Uses?

A

IRREVERSIBLE AChE Inhibitors
Organophosphates used as INSECTICIDES

Schradan = PHOSPHORAMIDE

  • prodrug/Inactive due to*
  • LACK OF A GOOD LEAVING GROUP (X)*
  • *Insects** have high oxidases –> toxic metabolite

Humans have N-dealkylation –> inactive metabolite

57
Q

Drug Type / Uses?

A

IRREVERSIBLE AChE Inhibitors
Organophosphates used as INSECTICIDES

THIOPHOSPHATES
P –> S = PRODRUG
need to bioactivated, insects have more reactive OXIDATIVE enzymes

Toxic Forms = PARAOXON + MALAOXON

58
Q

What is

2-PAM

Uses?

A

ANTIDOTE for OrganoPhosphate Poisoning

  • *2-PAM = Pralidoxime Chloride**
  • *RE-ACTIVATES AChE**

interacts with anionic site –> dissociates bond with serine site

ONLY EFFECTIVE PRIOR TO AGING PROCESS

PDAT5 CV (30 decks)

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