Presentation on Parasympathetic Nervous System

Autonomic Nervous system is a part of nervous system that controls and regulate the internal organs.
Sympathetic Nervous System: Release Adrenaline
Parasympathetic Nervous System: Release Acetylcholine
Pre & post ganglionic fibres of parasympathetic nerves liberate Ach.
Important Responses of Ach
Contraction of Smooth muscles
Cardiac Inhibition
Peripheral Vasodilation
Henry Dale, a British physiologist working in London in 1914, found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine.

1. PARASYMPATHETIC NERVOUS SYSTEM
OR
CHOLINERGIC NERVOUS SYSTEM

2. AUTONOMIC NERVOUS SYSTEM
•Partofnervoussystemthatcontrolsand
regulatetheinternalorgans.
Twotypes
•SympatheticNervousSystem:Release
Adrenaline
•ParasympatheticNervousSystem:Release
Acetylcholine

3. Cholinergic Neurotransmitter
Acetylcholine
•Pre&postganglionicfibresof
parasympatheticnervesliberateAch.
•ImportantResponsesofAch
1.ContractionofSmoothmuscles
2.CardiacInhibition
3.PeripheralVasodilation

4. Biosynthesis of ACh
•Achismajorneurotransmitterofpost
ganglionicsynapsesofcholinergicor
parasympatheticnerveending.CH
3
C
O
O
CH
2
CH
2
N
+
CH
3
CH
3
CH
3

5. •Achisbiosynthesizedinnerveterminal.
•AchissynthesizedbyCholineandAcetyl
coenzymewiththehelpofAcetycholine
transferase.
•Activetransportsysteminvolvespickingupof
cholinemoleculefromextrasynapticfluid.
•Thistransportisdependentuponintracellular
conc.ofNa+&K+ions.

6. •Cholineisacetylatedinthecytoplasmby
acetylcoenzymeAwhichisbiosynthesizedin
mitochondriapresentinthenerveterminal.
•Achisstoredinsynapticvesicles
•Whenimpulsereachestonerveterminal
depolarizationcausesactivationofCa
ionophore,allowsinfluxofCaions,rupturing
ofstoragevesiclestoreleaseofAch.

9. Ach getsquicklyhydrolysedby
Acetylcholinesterase(AChE),uponhydrolysis
AchisconvertedintoaceticacidandCholine.CH
3
C
O
O
CH
2
CH
2
N
+
CH
3
CH
3
CH
3
Choline+Acetyl Co
-
A
Chloineacetylase
Acetylcholine Release of ACh
Acetylcholinesterase
Choline + ACetic acid
OH CH
2
CH
2
N
+
CH
3
CH
3
CH
3
Choline
CH
3
COOH
Acetylcholine
Acetic acid

10. Cholinergic Receptor
•Acetylcholineactsonmorethanonetypeofreceptor.
•HenryDale,aBritishphysiologistworkinginLondonin1914,
foundthattwoforeignsubstances,nicotineandmuscarine,
couldeachmimicsome,butnotall,oftheparasympathetic
effectsofacetylcholine.
•ItwasfoundthatNicotinestimulatesreceptorsonskeletal
musclehowever,muscarinestimulatesreceptorsiteslocated
onlyatthejunctionbetweenpostganglionicparasympathetic
neuronsandthetargetorgan.

11. •Dalethereforeclassifiedthemanyactionsofacetylcholine
intonicotiniceffectsandmuscariniceffects.
•nicotinicreceptorscausesympatheticpostganglionicneurons
andparasympatheticpostganglionicneuronstoreleasetheir
chemicalsandskeletalmuscletocontract.
•Muscarinicreceptorsareassociatedmainlywith
parasympatheticfunctionsandstimulatesreceptorslocatedin
peripheraltissues(e.g.,glands,smoothmuscle).
•Acetylcholineactivatesallofthesesites.

13. MuscarinicReceptors

14. Nicotinic Receptors
•N1-Thesearefoundattheskeletalmuscleendplateandare
responsibleformediatingskeletalmusclecontractions.They
areactivatedspecificallybyphenyltrimethylammoniumand
inhibitedbytubocurarine.
•N2-Foundinganglioniccells,adrenalmedullarycells,the
spinalcord,andspecificpartsofthebrain.Theyare
predominantlyactivatedand inhibitedby
dimethylphenylpiperazineand hexamethonium.

15. MuscarinicActions Nicotinic Actions
Cardiac Inhibition
Peripheral Vasodilation
Constriction of eye pupil
Increased salivation
Contraction of peristaltic action
on GIT and urinary tract
Stimulation and maintainance
of tone of skeletal muscles

16. Chemical Features of AChCH
3
C
O
O
CH
2
CH
2
N
+
CH
3
CH
3
CH
3
Acetyl GroupEthylene bridgeQuaternary Ammonium group

17. Chemical Features of ACh
•ChemicallyAchisanesterofaceticacidandcholine
•Onthestructuralbasis,itoffers3sitesformolecular
modification,
1.Acetylgroup
2.Ethylenebridge
3.Quaternaryammoniumgroup
•Quaternaryammoniumgroupislinkedbyethylene
bridgetoanestergroup.
•FreeAChisrapidlyhydrolysedtoaceticacidand
cholinemoleculebycholinesteraseenzyme.

18. SAR
•Anychangeintheethylenebridgemayaffectthechemical
stabilityofACh.
•Cationicammoniumgroupisessentialformanifestationof
bothmuscarinicandnicotinicreceptoractivities.
•Quaternarynitrogenmaybereplacedbyarsenic,antimony,
phosphorousorsulphurwithoutlossofAChlikeactivity.
•Formaximalmuscarinicactivitythereshouldnotbemore
than4atomsbetweenNandterminalCatom.CH
3
C
O
O
CH
2
CH
2
N
+
CH
3
CH
3
CH
3
Acetylcholine

19. •Ifbulkysubstituentsareplacedonterminal
carbonatomofacetylgroup,these
substituentsblocktheaccessofAChtothe
receptor.Thisresultsinantimuscarinicactivity.
Eg.Benzilylcholine,Tropylcholine.CHC
H
5
C
6
H
5
C
6
O
OCH
2
CH
2
N
+
CH
3
CH
3
CH
3
CHC
H
5
C
6
HOH
2
C
O
OCH
2
CH
2
N
+
CH
3
CH
3
CH
3
Benzilylcholine Tropylcholine

20. Cholinergic Receptor
From SAR studies structure of cholinergic receptor is predicted as
Quaternary ammonium group forms electrostatic bond with
anionoicsite.
Ester forms H-bond at the esteraticsite.
Methyl group present on N atom along with terminal –CH3 are
bound to the receptor by both hydrophobic and van derwaalforcesCH
3
C
O
O
+
CH
2
CH
2
NCH
3
CH
3
CH
3
OH
-
Esteratic site Anionic site
+

21. •The binding assures a close fit of the molecule to
the receptor as shown below.
1.Region of Hydrophobic binding (Van derwaals
forces)
2.Region of H-bonding
3.Region of ionic bondingCH
3
COCH
2
CH
2
N
+
CH
3
CH
3
CH
3
O
O
N
H
H
1
1
2
1
3
CO
2
-

22. SAR of Parasympathomimeticagents
1.ModificationatQuaternaryammoniumgroup
Thetrimethylammoniumgroupistheoptimal
functionalrequirementfortheactivity.Thereare
followingexceptions.O
O
H
5
C
2
CH
2
N
N
CH
3
Pilocarpine
N
H
COOCH
3
Arecoline
N
N
CH
3
Nicotine

23. 2.ModificationofEthylenebridge
•Thereshouldnotbemorethan4atomsbetweennitrogenand
terminalcarbonatom.
•ReplacementofHatomofethylenebridgebyalkylgroupproduces
farlessactivecompound.
•Presenceofmethylgroupbetatothequaternarynitrogenatom
increasesmuscarinicactivity.
•Addedmethylgrouphinderstheattackofesteraseenzymethus
slowsdownenzymatichydrolysis.
•MethylgroupalphatotheNincreasesnicotinicactivity.CH
3
C
O
O
CH CH
2
N
+
CH
3
CH
3
CH
3
CH
3
Methacoline

24. 3. Modification of the Acylgroup
•When the acylgroup is substituted by its higher homologues
(propionyl, butyryletc.), less active compounds are formed.
•Cholineesters of aromatic or higher molecular weight acids
are cholinergic antagonist rather than agonists.
•When terminal methyl group is replaced by –NH2 group, is
potent cholinergic agent with both muscarinicand nicotinic
activities.NH
2
C
O
O
CH CH
2
N
+
CH
3
CH
3
CH
3
CH
3
Cl
-
Bethanechol chloride
Cl
-
NH
2
C
O
O
CH
2
CH
2
N
+
CH
3
CH
3
CH
3
Carbachol chloride

25. •Carbacholis stable to hydrolysis and has right size to fit the
cholinergic receptor.
•In carbacholterminal –CH3 of AChis replaced by –NH2 group,
while the size of the moeculeremains same as that of Ach. So,
the size of the molecule may be imp. to its activity.
•Similarly ether oxygen appears to be of primary importance
for high muscarinicactivity. As a result of these ethers of
cholineis examined for high muscarinicactivity.Cl
-
O CH
2
CH
2
N
+
CH
3
CH
3
CH
3
CH
2
CH
3
Choline ethyl ether

26. •Thereducedbiologicalactivityofcompoundsinwhichoxygen
isreplacedbysulphur.Eg.Thiomuscarine.BecauseSatomhas
lessabilitytoformH-bondwiththereceptor.N
+
CH
3
CH
3
CH
3
S
CH
3
OH
Thiomuscarine
X
-