2. Nervous System
Because of its wide and important involvement,
understanding Nervous system is important to treat many
diseases
Functions –
• Totransmit signals to and
from
body organs or cells to carry
out
o Heartbeat, Respiration
o Digestion, Hormone
secretion
o Movement, body pressure
• Toprocess sensory
information
• Logic, Decision and Memory
4. Two types of Autonomic NS
Parasympathetic NS
(Acetylcholine)
Sympathetic NS
(Adrenaline)
Makes
body
ready for
fight or
flight
Makes
body
ready for
rest
5. Sympathetic Vs
Parasympathetic
• SYMPATHETIC
Fight orFlight
• IncreaseBP& HR, glucose
perfusion
to skeletal muscles,Mydriasis,
Bronchodilatation
• PARASYMPATHETIC
Rest and Digest
•Miosis,decreasedHR, BP,bronchia
secretion, Insulinrelease, Digestion,
6. SitesofCholinergicTransmission–In
Brief
Acetylcholine (ACh)ismajor neurohumoral
transmitter atautonomic, somaticand central
nervoussystem:
1. All preganglionic sites (Both Parasympatheticand
sympathetic)
2. All PostganglionicParasympatheticsites and
sympathetic to sweat glandand some bloodvessels
3. SkeletalMuscles
4. CNS:Cortex,Basalganglia, spinal chord andothers
ParasympatheticStimulation – Acetylcholine (Ach)
releaseat neuroeffector junction - biologicaleffects
Sympathetic stimulation –Noradrenaline (NA) at
neuroeffector junction - biologicaleffects
9. Chemistry of
Ach
• Cholinergics refer to the part of Nervous system that utilize
Acetylchlonine (Ach) as a neurotransmitter. It is key NT in
the parasympathetic NS
• A unique feature of Ach is that the same molecule can bind
with two different receptors (muscarinic and nicotinic
receptor) using different conformation.
Acetylcholine
Acetyl Choline
10. Physio-Chemical properties of Ach
• It is ester of acetic acid and choline
• It is soluble in water due to salt form at Nitrogen
• In solid form it is stable but in solution, the ester group gets hydrolyzed
(ie ester group turns into acid and alcohol).
• If acid or base is present, as in stomach, then rate of hydrolysis is so fast that it
prevents oral dosing of Ach
• Even if we prepare it’s solution in neutral water and inject in blood so as to bypass
the acidic stomach, an ester hydrolyzing enzyme called butrylcholinesterase
significantly degrades it s that the pharmacological response is very weak
• Even if it was administered in stable form, It’s ionic ammonium
group prevents good penetration across the lipophillic cell wall
• This chemical property makes it a weak agonist plus since it is non- selective
agonist of Muscarinic and Nicotinic
• (Thus having no ester group and no ionic amine is an approach tp making more
stable and strong Ach agonist. However selectivity is a different issue)
15. H3C O
Acyloxy
group
O
CH2 CH2 N(CH3)3
Quaternary
Ammonum group
Ethylene
group
General strategy for creating SAR of cholinergics as
Muscarinic agonist
• Cholinergic drugs mimic action of Ach on Muscarinic or
nicotinic receptors and produce the same effect as Ach but in
greater magnitude
• A general strategy of making an agonist is to use the
original compound, in this case Ach, as a framework
16. Modification of quaternary Ammonium group
a) Presence of nitrogen in quaternary ionic form is
important for agonist activity. Replacement of
Nitrogen with other elements such as Sulphur,
Arsenic and Phosphorous reduces activity
b) Presence of three methyl group is needed for agonist
activity. Changing the three methyl group by higher
alkanes or Hydrogen also causes loss of activity
17. Valency
S = 4
P = 3
Ar = 3
N =3
Replacement with sulphur removes the + charge and causes reduced activity
Replacement with Arsenic or Phosphorous maintains + charge but still reduces
activity
Only this has good
potency
Conclusions:
1) positive charge needed
2) Positive charge should be on Nitrogen only
3) Charge on Nitrogen only possible when it bonded to 4 atoms ie quaternary form needed
18. • If R = methyl,(CH3) --> active
• If R = ethyl (C2H5) --> antagonist!
• If R = propyl (C3H9) and higher alkyls --> inactive
• If only one of the R = ethyl or propyl active but less potent
than Ach
• If any or all R = H activity goes on decreasing
19. 2) Change in the Ethylene Group
c) A “rule of five” idea states that there should be no more
than 5 atoms between the Nitrogen and the terminal
Hydrogen
As the chain length increased from two, activity is rapidly
lost.
N
O
H
H
H
1
O
3
2
4
5
C
This tells us
about the
relative size of
binding site
20. d) Inclusion of methyl group in the ethylene carbons can
alter selectivity
• Methyl inclusion in β carbon relative to N retains potency of
Ach and more selective to muscarinic receptor. This
compound is called methacholine and used clinically
• Methyl inclusion in α carbon relative to N reduces potency
but makes more selective to nicotinic receptor. This is not used
clinically
21. •Methyl group in Beta carbon
•As potent as Ach
•Selective to Muscarinic receptor
•Used clinically
Methacholine
H3C O
O
CH CH2 N(CH3)3
CH3
22. 3) Modifications to the Acetoxy group
e) Substituting the Acetyl with higher homologous group such as
propionyl or butyryl Reduces activity.
R
O
O CH2 CH2 N(CH3)3
If R = propionyl (C3H7), butyrl (C4H9)
or
higher than activity is reduced
23. f) The ester group isn’t mandatory as quanternary
amine group but an oxygen atom is required in this
region
• Since ester group makes it liable to hydrolysis, alternate groups
were included and found that replacing the ester with
carbamate, ether or ketone function resists hydrolysis
while maintaining activity
24. SAR of cholinergics
1. Presence of nitrogen in quaternary ionic form is
important for agonist activity
2. Presence of three methyl group in Nitrogen is needed for
agonist activity
3. A “rule of five” idea states that there should be no more than 5
atoms between the Nitrogen and the terminal Hydrogen
4. Inclusion of methyl group in beta carbon to N makes muscarinic
selective in alpha carbon to N makes nicotinic selective
5. The ester group isn’t mandatory as quanternary amine group
but an oxygen atom is required in this region
6. Replacing the ester with carbamate, ether or ketone function
resists hydrolysis while maintaining activity
H3C O CH2 CH2 N(CH3)3
Acyloxy
group
O
Quaternary
Ammonum group
Ethylene
group
