Fundamentals of Neurochemistry

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Organization of the nervous system
PERIPHERAL (divided into autonomic and somatic)
Autonomic nervous system
Part of the PNS
Divided into sympathetic, enteric, and parasympathetic nervous systems
Somatic nervous system
Part of the PNS
Associated with muscles and voluntary control of the movements
5 characteristics of neurotransmitters
1. Chemical must be synthesized and stored in the pre-synaptic cleft

2. Must be released upon stimulation

3. Must produce biological response in post-synaptic cell

4. Must have defined post-synaptic receptor

5. There must be a mechanism of elimination

3 main mechanisms of elimination of neurotrasmitters
1. Reuptake
2. Metabolism
3. Diffusion (slow and not usually common)
Compound with single amine group in the molecule

1. Catecholamines
2. Indolamine

Contains a benzene ring with 2 OH groups in ortho position

1. Norepinephrine/epinephrine
2. Dopamine

Indole compound with that has an amino group

1. Serotonin
2. Melatonin

Amino acid neurotransmitters
Most neurotransmitters are water-soluble

Most are charged, and they are transmitted to aqueous environment

They are “small” molecules

There must be some active transport needed for re-uptake of neurotransmitters (since they are water soluble)

Synthesis of Ach
Acetyl CoA + Choline ⇒ ***CHOLINE ACETYLTRASNFERASE*** ⇒ Ach
Exists in both PNS and CNS

Can be either inhibitory or excitatory

Ester bond represents instability

Quaternary ammonium ion is responsible for constant charge, thus increasing the water solubility

It may be taken back to the presynaptic region, but in order to do so, hydrolysis is needed (this is a way of saving energy from making new Ach)

There are NO transporters that do this function, so there must be an enzyme that carries out this function

Ach acidity
Quaternary ammonium cation gives a permanent + charge on the N

So, it most likely won’t gain or lose a proton, regardless of the pH of its environment, and consequently is neither acidic nor basic

Degradation of Ach
aka hydrolysis

Ach breaks into acetyl group + choline group by AChE (acetylcholine esterase)

1. Has Serine hydroxy portion, which attacks the carbonyl carbon to carry out hydrolysis

2. It has a pretty short half-life (making acetyl interface), thus making Ach to quickly hydrolyzed to re-activate the enzyme, leading to release of acetic acid

3. It is related to nerve gas (e.g. Vx, which is in a liquid form and easy to carry since they are not really volatile)

Examples of nerve gas toxins
Vx (in liquid form; not so volatile, so makes it easy for transport)

Organo-phosphates like SOMAN

How SOMAN nerve gas toxins works
1) SOMAN, once inhaled or absorbed through the skin, looks for AChE

2) This results in attack of the phosphate of SOMAN by the OH-serine group of the AChE

3) It results in longer half-life, where AChE is no longer active enough to degrade Ach

4) You get accumulation of Ach, which can lead to respiratory failure and death

Natural product

It’s a muscarinic, competitive antagonist

When there has been accumulation of Ach due to toxic gas, it works as an antidote to block interaction of Ach with the receptor

So even if there are a lot of Ach molecules, if Ach cannot interact with the receptors, then there won’t be negative consequences

2 main classes of Ach receptors
1. Nicotinic (uses ion channels)
2. Muscarinic (uses GPCR)

***Nicotine is the agonist of Ach on the nicotinic receptor, and muscarine is the agonist of Ach on the muscarinic receptor

Characteristics of norepinephrine
It has R stereochemistry

Highly water soluble


The OH next to primary amine (pKa ~8.6) is not easily de-protonated, and it is not considered acidic

OH on catechol group (pKa ~9) is acidic, because of conjugation

Responsible for ergotropic vigilance

Ergotropic vigilance
Energy expanding system (sympathetic division of the PNS)

“Fight of flight”

Characteristics of epinephrine
Also has R stereochemistry

Also highly water soluble


The OH next to secondary amine (pKa ~9.16) is even less likely to be de-protonated than the OH in norepinephrine, because secondary amine makes lone pairs more easily available (less acidic)

OH on catechol group (pKa around 9) is acidic, because of conjugation

Biosynthesis pathway
Major elimination pathway of adrenregic hormones
***Re-uptake (minor)
***Diffusion (minor)
Metabolism of adrenergic hormones
2. MAO, then ALDH
aka Catechol-O-methyltransferase

Puts a methyl group to the OH group on the catechol that’s meta to where the beta OH is attached to (specific binding)

Can either happen before or after MAO

Usually forms an inactive compound

1. MAO
The monoamine is taken away by oxidase
aka Aldehyde dehydrogenase

It converts an aldehyde group to COOH (because aldehyde group is inactive)

What are adrenergic receptors classified by?
Binding affinity
Alpha-adrenergic receptors
Epinephrine ≥ Norepinephrine >>> Isoproterenol
Beta-adrernergic receptors
Isoproterenol > Epinephrine ≥ Norepinephrine
It is a catecholamine

Has no chiral center

Highly water soluble, so it will NOT cross BBB (there’s no transport mechanism)

Primary amine has pKa ~9.99

Synthesis of dopamine
*Look at the biosynthesis pathway
Polar, so can’t cross BBB by itself

HOWEVER, there is an active transport protein for this, so it can be used for disease like Parkinson’s Disease

It has a pretty short half-life of 50 minutes

DOPA decarboxylase
It is both in CNS and PNS
It is an amino acid decarboxylase
Metabolism of dopamine
1. Dopamine-B-hydroxylase
2. MAO/ALDH (same as adrenergic hormones), and then catechol-O-methyltrransferase
Dopamine metabolites
Norepinephrine when using dopamine-B-hydroxylase

Homovanillic acid when using MAO/ALDH + catechol-O-methyltransferase

Dopamine receptors
5 types; all GPCR

Inhibitory receptors: D1 and D5 (increases the cAMP level)

Stimulatory receptors: D2~D4 (decreases the cAMP level)

Why Levodopa/Carbidopa combination is recommended
Carbidopa exists in both CNS and PNS

HOWEVER, it ONLY recognizes decarboxylase at the peripheral system and prevents PERIPHERAL conversion of Levodopa

Carbidopa prevents decarboxylation of Levodopa until Levodopa reaches the brain

Both combined, half-life will be extended to 1.5 hours compared to when using just the Levodopa

Serotonin (aka 5 HT)
Monoamine – indolamine

NH2 group (pKa ~10)
OH group on the indole ring (pKa ~9)

This is also highly water-soluble

Present in CNS and GI tract

Acidic (since pKa > pH)

Anti-depressant drugs elevate the level of serotonin, usually by inhibiting the re-uptake of serotonin

Responsible for trophotropic impulse

Trophotropic impulse
Nutrient accumulating systems (parasympathetic division of the PNS)

“Rest and digest”

Synthesis of Serotonin
Main mechanism of elimination of serotonin
Serotonin reuptake mechanism
1. MAO
Serotonin receptors
There are at least 14 different subtypes

Just know that most of them are GPCR channels
(***exception: 5HT 3, which uses ion channel)

Categories: Neurochemistry