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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
Cholinergic Blocking Agent = AntiMuscarinic **Requirements / Optimal Binding** @ **_R1_**
**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
Cholinergic Blocking Agent = AntiMuscarinic **Requirements / Optimal Binding** @ **_R2_**
**R2 = _Hydrophobic_** or **Aromatic Ring** (cycloalkyl) Most potent = hydrophobic ## Footnote ***_size LIMITED_***
27
Cholinergic Blocking Agent = AntiMuscarinic **Requirements / Optimal Binding** @ **_R3_**
R3 = **H / OH / Carboxamide / HydroxyMethyl** for **_HYDROGEN BONDING_** ## Footnote ***_can NOT tolerate BULK_***
28
Cholinergic Blocking Agent = AntiMuscarinic **Requirements / Optimal Binding** @ **_X_**
**X = _Ester / Ester / Hydrocarbon_**
29
**Homatropine & Tropicamide** **Type / Special fxn**
**AntiMuscarinics** w/ ***_SHORTER Duration of Action_*** vs **Atropine**
30
**MethScopolamine / Ipratropium / Tiotropium** Type / Special fxn
**_QUATERNIZED_ AntiMuscarinics** Quaternized = **N+** that ***_do NOT cross the BBB_***
31
**Pirenzepine / Darifenacin / Solifenacin** Type / Special
**Muscarinic antagonist** w/ **RECEPTOR SELECTIVITY** ## Footnote **Pirenzepine = M1** **Darifenacin & Solifenacin = M3**
32
**What Drug & Type?**
**_PAROXETINE_** antidepressant with **high affinity to Muscarinic Receptors (mAChRs)** * *R1** = **Phenyl w/ FLUOURINE @ PARA position** * still tolerable --\> has AC EFFECTS*
33
**What drug & type?**
* *_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
**AntiMuscarinic Agents with** **AC Side Effects**
_Still have AC effects_ ## Footnote **Oxypenomium** **Glycopyrrolate** **Clidnium Bromide** **Homatropine Methyl Bromide**
35
**AntiMuscarinic Agents for** **PARKINSON'S DISEASE**
Parkinson's disease **= ↓****Dopamine**--\>**_Chemical Imbalance_** **Tremor + Rigid Muscles** **AC drugs** --\> ↓**ACh** **Dopamine levels closer to ACh levels = BALANCE** **_Trihexylphenidyl_** **_Orphenadrine_** **_Benztropine_** **_Biperiden_**
36
**Drugs with POTENT AC SIDE EFFECTS**
**_Amitryptiline_** **_Diphenhydramine_** **_Clozapine_** **_Disopyramide_**
37
**Drug Type?** **Hexamethonium / Tetraethylammonium**
* *_COMPETITIVE Nicotinic ANTAGONIST_** * *Ganglionic Receptor Blockers** Hexamethonium + Tetrathylammonium
38
**Drug Type?**
* **_NON-COMPETITIVE_*** * *Nicotinic ANTAGONIST** **Ganglionic Receptor Blockers** **Trimethaphan Camsilate** = **SHORT ACTING** used for **neurosurgical procedures** which have **excessive bleeding**
39
* *Drug Type?** * *DECamethonium** (C10) 10-12 unsubstituted methylene groups **Hexamethonium C6 = ganglionic blocker**
* *_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
**Drug Type?** **d-Tubocurarine** / **Gallamine** / **Pancuronium**
* *_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
* *MoA of * _IRREVERSIBLE_*****AcetylCholineEsterase (AChE) Inhibitors** OrganoPhosphates Drugs = Diisopropyl Fluorophosphate & Echotiopate Chemical Warfare = Tabun / Sarin / Paraoxon Insecticides = Thiophosphates = Parathion / Malathion
* **_Inhibition of AChE_*** * *ACh** --/--\> **Choline + Acetic Acid** = ↑**ACh in Synaptic Cleft** _**PHOSPHRYLATED** ENZYME INTERMEDIATE_ **Hours-Days** = "**Aging"**
42
**MoA of _REVERSIBLE_****AcetylCholineEsterase (AChE) Inhibitors** Carbaryl Physostigmine / Neostigmine Pyrostigmine / Rivastigmine
* **_Inhibition of AChE_*** * *ACh** --/--\> **Choline + Acetic Acid** = ↑**ACh in Synaptic Cleft** _**CARBAMOYLATED** ENZYME INTERMEDIATE_ **15-20 min regeneration** = **Slow**
43
**Reversible AChE Inhibitors** ## Footnote **Drugs + Features**
**_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
**Drug Type / Features**
**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
**Drug Type / Features**
**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
**Drug Type / Features**
**_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
**Which Carbamate Ester-Type** **REVERSIBLE AChE Inhibitors** * **_LACK CENTRAL ACTIVITY_*** * &* * *WHY??**
**_NEOSTIGMINE**_ + _**PYROSTIGMINE_** * no central activity due to:* * *IONIZATION** = **Has Charge --\> can't enter BBB**Attach Images
48
**Drug Type / Features**
**_RIVASTIGMINE_** = **REVERSIBLE AChE Inhibitor** Carbamate Ester-Type * **_PSEUDO-Irreversible_*** * *\<10 hours** --\> *slow dissociation of carbamylated enzyme* **Centrally Acting** --\> **_Alzheimers Disease_**
49
**MoA of** _***IRREVERSIBLE* AChE Inhibitors**_
* *_AGING PROCESS_** * *H2O** --\> **R2O** **Side** = **Aging** --\> ***_IRREVERSIBLE_*** * Strengthened BOND = can NOT be hydrolyzed* If added to the other side, **Hydrolysis**
50
* *SAR** of ***_IRREVERSIBLE_*** **_AChE Inhibitors_** * *ORGANOPHOSPHATES** ## Footnote **"A"**
* *_A = Sulfa_** --\> **_PRODRUG_** * requires BIOLOGICAL ACTIVATION* before becoming an **effective AChE inhibitor** **_A = O**_ --\> _**Active Drug_**
51
* *SAR** of ***_IRREVERSIBLE_*** **_AChE Inhibitors_** * *ORGANOPHOSPHATES** ## Footnote **"X"**
**X = GOOD LEAVING GROUP** **-F / -CN** **-ThioMalate** **-P-NitroPhenyl**
52
* *SAR** of ***_IRREVERSIBLE_*** **_AChE Inhibitors_** * *ORGANOPHOSPHATES** ## Footnote **R1**
**R1** = **ALKOXYL** -ORR
53
* *SAR** of ***_IRREVERSIBLE_*** **_AChE Inhibitors_** * *ORGANOPHOSPHATES** ## Footnote **R2**
**R2 = Alkoxyl / Alkyl / 3\*Amine** **-ORR** -**RR** **-NR3**
54
**Drug Type / Uses?**
* *_*IRREVERSIBLE* AChE Inhibitors_** * *OrganoPhosphates** **Diisopropyl Fluorophosphate** **EchoThiopate** used for **local glaucoma treatment** --\> ~4 weeks
55
**Drug Type / Uses?**
**Tabun / Sarin / Paraoxon** * *_*IRREVERSIBLE* AChE Inhibitors_** * *OrganoPhosphates** **GASES & CHEMICAL WARFARE AGENTS** Phosphateesters are very STABLE to hydrolysis
56
**Drug Type / Uses?**
**_*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
**Drug Type / Uses?**
**_*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
**What is** **_2-PAM_** **Uses?**
**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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