neurotransmitters

1. Neurotransmitters

2. Learning outcomes
 To describe the chemistry of different types of
neurotransmitters from the adrenergic and cholinergic
receptors.
 To describe the biosynthesis in terms of their structure
and mechanism of action.
 To describe the metabolic pathway of neurotransmitters
 To discuss SAR and physiochemical properties of
neurotransmitters

3. Neurotransmitters
 Neurotransmitters are molecules used to signal cells
within the body.
 They are released via exocytosis in a synaptic vesicle,
which travels across the synaptic cleft, and then binds to
a receptor on the post-synaptic cell.
 This binding causes either excitatory or an inhibitory
current through ion channels in the post-synaptic cell,
which depolarizes or hyperpolarizes it, respectively.
 With enough depolarization, a neuron will signal (fire an
action potential).
 Enzymes within the synaptic cleft inactivate
neurotransmitters, which are then taken back to the pre-
synaptic cell for re-usage, or destroyed.

4. Neurotransmitters
 Adrenergic/sympathetic neurotransmitters
Adrenaline (epinephrine) and noradrenaline
(norepinephrine)
Dopamine
 Cholinergic/parasympathetic neurotransmitters
Acetyl Choline
 Central neurotransmitters
Serotonin(5-Hydroxy tryptamine)
GABA(γ-Amino Butyric acid)
Glutamic acid

5. Adrenergic neurotransmission
 Norepinephrine
Postganglionic sympathetic neurotransmitter
Requires sympathetic nerve stimulation
Released from sympathetic nerve endings to synaptic
cleft
Interacts with specific presynaptic and postsynaptic
adrenergic receptors.

6. Norepinephrine chemical structure

7. Epinephrine and norepinephrine
 Epinephrine and norepinephrine belong to the chemical class of
substances known as catecholamines.
 Epinephrine/norepinephrine has many functions in the body,
regulating heart rate, blood vessel and air passage diameters, and
metabolic shifts; epinephrine release is a crucial component of the
fight-or-flight response of the sympathetic nervous system
 This name is given to these compounds because they contain an amino
group attached to an aromatic ring that contains two hydroxyl groups
situated ortho to each other.

8. Stability of catecholamines
 They are susceptible to oxidation and give ortho-quinone like
compounds.
 Solutions of catecholamine drugs are stabilized by the addition
of an antioxidant drugs such as ascorbic acid or sodiumbisulfite.
HO
HO
[O]
O
O
Catechol O-Quinone

9. Stereochemistry of epinephrine and
norepinephrine
 Epinephrine(EP) and norepinephrine
(NE) possess a chiral carbon atom.
 Exist as an enantiomeric pair of
isomers.
 The enantiomer with R configuration
is biosynthesized by body and possess
biological activity.

10. Chemistry of catecholamines
 Catecholamines are polar substances that contain both acidic
(aromatic hydroxyls) and basic (aliphatic amine) functional groups.
 The pKa values for the epinephrine cation 8.7 (phenolic hydroxyl
group) and 9.9 (protonated amino group) attributed respectively.

11. Relative ionization of Epinephrine(EP) and
Norepinephrine(NE)
 The relative ionized and non-ionized species of NE and
EP at pH 7.4:
 The cationic form(A) is present greater than 95% for both
catecholamines.
 The zwitterionic form(B) (the aliphatic amine is protonated
and one of the phenolic hydroxyl groups) is ionized and is
present up to 3%.

12. HO
HO
OH
A
NH2R
+
O
O
-
+
NH2R
OH
H
B

13. Biosynthesis

14. • Catecholamine synthesis is inhibited by alpha-
Methyltyrosine, by inhibiting tyrosine hydroxylase
• Alpha-methyltyrosine is used in management of
pheochromocytoma

15. Catabolism
 They have a half-life of approximately a few minutes when circulating in the
blood.
 Monoamine oxidase (MAO) is the main enzyme responsible for degradation of
catecholamines.
 Methamphetamine and MAO inhibitors (MAOIs) bind to MAOs to inhibit their
action of breaking down catecholamines.
 Amphetamine not only cause a release of dopamine, epinephrine and
norepinephrine into the blood stream, but also keep it working there for a
long time.

17. Neurotransmitter reuptake
 Neurotransmitters uptake into neuron
and into extraneuronal tissues, diffusion
away from synapse.
 Primary mechanism for the termination
mechanism of action of NE is reuptake of
catecholamine into the nerve terminal.
 This process involves a Na+/Cl-
dependent transmembrane transporter
that has high affinity for NE.

18. Dopamine
 It is chemically known as phenethylamine.
HO
HO
NH2
Dopamine

19. Dopamine inactivation and reuptake
 Dopamine is inactivated by reuptake via the
dopamine transporter, then enzymatic breakdown
by catechol-O-methyl transferase (COMT) and
monoamine oxidase (MAO).
 Dopamine that is not broken down by enzymes is
repackaged into vesicles for reuse.
 Dopamine may also simply diffuse away from the
synapse, and regulate blood pressure.

21. Cholinergic neurotransmission
 Acetyl choline(Ach): an ester of acetic acid and choline with
chemical formula CH3COOCH2CH2N+(CH3)3.
 Both peripheral and central nervous system neurotransmitter.
 2-acetoxy-N,N,N-trimethylethanaminium

22. Synthesis and degradation
 Acetylcholine is synthesized in certain
neurons by the enzyme cholineacetyl
transferase from the compounds choline
and acetyl CoA.
 The enzyme acetylcholine esterase
converts acetylcholine into the inactive
metabolites choline and acetate.
 This enzyme is abundant in the synaptic
cleft, and its role in rapidly clearing free
acetylcholine from the synapse is essential
for proper muscle function.
H3C
O
SCoA
+ N
CH3
CH3
CH3
+
HO
Acetyl CoA
Choline
Cholineacetyl transferase
H3C O
O
+
CH3
CH3
CH3
N
Acetyl choline

24. g-Amino Butyric Acid (GABA)
α β g
Central Neurotransmitters
• γ-Aminobutyric acid or GABA is the chief
inhibitory neurotransmitter in the
mammalian central nervous system.
• It plays a role in regulating neuronal
excitability throughout the nervous system.
• In humans, GABA is also directly
responsible for the regulation of muscle
tone

25. Biosynthesis of GABA

26. 5-Hydroxy Tryptamine(Serotonin)
 Serotonin or 5-hydroxytryptamine (5-HT) is a
monoamine neurotransmitter.
 Biochemically derived from tryptophan, serotonin is
primarily found in the gastrointestinal (GI) tract,
platelets, and in the central nervous system (CNS) of
animals and humans.
 It is popularly thought to be a contributor to feelings
of well-being and happiness
1
2
3
4
5
3-(2-aminoethyl)-1H-indol-5-ol

27. Biosynthesis

28. Metabolism

29. Histamine
 Histamine is an organic nitrogen compound acting as a
neurotransmitter
 Histaminergic action is known to modulate sleep.
Classically, antihistamines (H1 histamine receptor antagonists)
produce sleep.
2-(1H-imidazol-4-yl)ethanamine

30. Histamine biosynthesis
 Histamine is derived from the decarboxylation of the
aminoacid, l-histidine
 Reaction is catalyzed by the enzyme l-histidine
decarboxylase.
l-histidine Histamine
l-histidine decarboxylase

31. Glutamic acid
 Glutamate is the most abundant excitatory neurotransmitter in the
vertebrate nervous system
 One of the non-essential amino acids
 glutamate is involved in cognitive functions like learning and memory in
the brain
(2S)-2-aminopentanedioic acid

32. THANK YOU