2/3 - CHEMISTRY OF THE CHOLINERGIC NERVOUS SYSTEM Flashcards
NVP
Target:
Biostynthesis of Acetylcholine
Lead compound for
Inhibiting ChAT
Imitates Acetyl-CoA –> blocks Choline AcetylTransferase
Hemicholinium-3
HC-3
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
TriethylCholine
TEC
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
L-Vesamicol
Inhibitor of Vesicular ACh Uptake
non-competitive inhibitor
Binds to allosteric site –> prevents ACh binding
Drugs that target:
Release of ACh
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
Tetracycline
Target:
Release of ACh
Complex Binding with CALCIUM
Ca2+ induces vesicles to fuse w/ the membrane
- *Tetracycline** –> binds the free calcium
- *↓Ca2+ concentration**
Botulinum Toxin
Target:
BLOCKS Release of ACh
from NM junctions
Cleaves SNAP-25
protein essential for docking & release of ACh from vesicles
Beta-Bungarotoxin
Target:
PROMOTE the release of ACh
VVV
EXHAUSTION of ACh
stores in the nerve terminal
Choline Alfoscerate
Alpha-GPC
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
How does Choline Alfoscerate enter the BRAIN?
(Alpha-GPC)
↑ACh Concentration
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
Muscarinic Antagonists
AKA - Antichoinergics
Naturally Occuring Tropine Alkaloids:
Atropine + Scopolamine
from
Deadly Nightshade = Belladonna
Synthetic Derivitives
Homatropine + Tropicamide
Quaternized = Do NOT cross BBB
Methscopolamine / Ipratropium / Tiotropium
Where are there
ONLY NICOTINIC RECEPTORS?
- *NEUROMUSCULAR**
- *ACh Receptors**
ACh Receptors of the:
CNS & Autonomic System have Both Muscarinic & Nicotonic
What type of receptor are
NICOTINIC RECEPTORS?
ION GATED CHANNELS
VVV
Change in Ion Concentration
AcetylCholine = Neurotransmitter
for BOTH Muscarinic & Nicotinic
What type of receptor are
MUSCARINIC RECEPTORS?
GPCR
7-Transmembrane helical structure w/a-b-y subunits
VVV
Cascade of Chemical Reactions
AcetylCholine = Neurotransmitter
for BOTH Muscarinic & Nicotinic
How do Nicotinic Cholinergic Receptors work?
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
How do MUSCARINIC RECEPTORS work?
Stimulation vs Inhibitory
STIMULATION
M1 / M3 / M5 (ODDS)
Lead to PLC –> CALCIUM RELEASE
- INHIBITORY*
- *M1 / M4**
- *AC** –> _↓cAMP RELEASE_
Modifications to Acetylcholine for Cholinergic Agonists:
What conformation of ACh is PREFERRED?
+TRANS +AC
5x more potent when CONFORMATIONALLY RESRTRICTED
compared to flexible ACh
cis = inactive
-ac / trans = 1/50
Modifications to Acetylcholine for Cholinergic Agonists:
- *Quaternary Ammonium Group**
- *What improves binding / activity?**
+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
Modifications to Acetylcholine for Cholinergic Agonists:
- *ACETYL**
- *What improves binding / activity?**
Acetyl** –> **CARBOMYL
ORALLY ACTIVE
Carbomyl is:
- less electrophilic* & more stable to hydrolysis
- less readily hydrolyzed by GASTRIC acid*
(CH3 –> NH2)
Modifications to Acetylcholine for Cholinergic Agonists:
- *ETHYLENE BRIDGE**
- *What improves binding / activity?**
BETA-METHYL SUBSTITUTION
Muscarinic Agonist
B-M
- *a-methyl substitution**
- *Nicotinic Agonist**
double methyl sub = INACTIVE
Drug & Class?
CARBACHOL
no a/b substitution = both nicotinic & muscarinic agonist
Acetyl (of ACh) –> CARBOMYL = ORAL ACTIVITY
Drug & Class?
BETHANECHOL
treatment of urinary retention & ab distention
B-substitution = Muscarinic Agonist
Acetyl (of ACh) –> CARBOMYL = ORAL ACTIVITY
What Drug & Class?
- *ATROPINE**
- *Naturally occuring TROPINE alkaloid**
- similar to ACh but bind better*
Muscarinic Antagonist = Anticholinergic = AntiMuscarinic
What Drug & Class?
SCOPOLAMINE
- *Naturally occuring TROPINE alkaloid**
- similar to ACh but bind better*
Muscarinic Antagonist = Anticholinergic = AntiMuscarinic
(3 x atropine, also a racemate)
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
Cholinergic Blocking Agent = AntiMuscarinic
Requirements / Optimal Binding
@
R2
R2 = Hydrophobic or Aromatic Ring (cycloalkyl)
Most potent = hydrophobic
size LIMITED
Cholinergic Blocking Agent = AntiMuscarinic
Requirements / Optimal Binding
@
R3
R3 = H / OH / Carboxamide / HydroxyMethyl
for
HYDROGEN BONDING
can NOT tolerate BULK
Cholinergic Blocking Agent = AntiMuscarinic
Requirements / Optimal Binding
@
X
X = Ester / Ester / Hydrocarbon
Homatropine & Tropicamide
Type / Special fxn
AntiMuscarinics
w/
SHORTER Duration of Action vs Atropine
MethScopolamine / Ipratropium / Tiotropium
Type / Special fxn
QUATERNIZED AntiMuscarinics
Quaternized = N+
that
do NOT cross the BBB
Pirenzepine / Darifenacin / Solifenacin
Type / Special
Muscarinic antagonist
w/
RECEPTOR SELECTIVITY
Pirenzepine = M1
Darifenacin & Solifenacin = M3
What Drug & Type?
PAROXETINE
antidepressant with high affinity to Muscarinic Receptors (mAChRs)
- *R1** = Phenyl w/ FLUOURINE @ PARA position
- still tolerable –> has AC EFFECTS*
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*
AntiMuscarinic Agents with
AC Side Effects
Still have AC effects
Oxypenomium
Glycopyrrolate
Clidnium Bromide
Homatropine Methyl Bromide
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
Drugs with
POTENT AC SIDE EFFECTS
Amitryptiline
Diphenhydramine
Clozapine
Disopyramide
Drug Type?
Hexamethonium / Tetraethylammonium
- *COMPETITIVE Nicotinic ANTAGONIST**
- *Ganglionic Receptor Blockers**
Hexamethonium + Tetrathylammonium
Drug Type?
- NON-COMPETITIVE*
- *Nicotinic ANTAGONIST**
Ganglionic Receptor Blockers
Trimethaphan Camsilate = SHORT ACTING
used for neurosurgical procedures which have excessive bleeding
- *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
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
- *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”
MoA of
REVERSIBLEAcetylCholineEsterase (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
Reversible AChE Inhibitors
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
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
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
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
Which Carbamate Ester-Type
REVERSIBLE AChE Inhibitors
- LACK CENTRAL ACTIVITY*
- &*
- *WHY??**
NEOSTIGMINE** + **PYROSTIGMINE
- no central activity due to:*
- *IONIZATION** = Has Charge –> can’t enter BBBAttach Images
Drug Type / Features
RIVASTIGMINE = REVERSIBLE AChE Inhibitor
Carbamate Ester-Type
- PSEUDO-Irreversible*
- *<10 hours** –> slow dissociation of carbamylated enzyme
Centrally Acting –> Alzheimers Disease
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
- SAR** of *_IRREVERSIBLE_ AChE Inhibitors
- *ORGANOPHOSPHATES**
“A”
- *A = Sulfa** –> PRODRUG
- requires BIOLOGICAL ACTIVATION* before becoming an effective AChE inhibitor
A = O** –> **Active Drug
- SAR** of *_IRREVERSIBLE_ AChE Inhibitors
- *ORGANOPHOSPHATES**
“X”
X = GOOD LEAVING GROUP
-F / -CN
-ThioMalate
-P-NitroPhenyl
- SAR** of *_IRREVERSIBLE_ AChE Inhibitors
- *ORGANOPHOSPHATES**
R1
R1 = ALKOXYL
-ORR
- SAR** of *_IRREVERSIBLE_ AChE Inhibitors
- *ORGANOPHOSPHATES**
R2
R2 = Alkoxyl / Alkyl / 3*Amine
-ORR
-RR
-NR3
Drug Type / Uses?
- *IRREVERSIBLE AChE Inhibitors**
- *OrganoPhosphates**
Diisopropyl Fluorophosphate
EchoThiopate
used for local glaucoma treatment –> ~4 weeks
Drug Type / Uses?
Tabun / Sarin / Paraoxon
- *IRREVERSIBLE AChE Inhibitors**
- *OrganoPhosphates**
GASES & CHEMICAL WARFARE AGENTS
Phosphateesters are very STABLE to hydrolysis
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
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
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
