Fundamentals of Neurochemistry

CENTRAL
PERIPHERAL (divided into autonomic and somatic)

Part of the PNS
Divided into sympathetic, enteric, and parasympathetic nervous systems

Part of the PNS
Associated with muscles and voluntary control of the movements

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

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

GABA
Glutamate

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)

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

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

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)

Vx (in liquid form; not so volatile, so makes it easy for transport)

Organo-phosphates like SOMAN

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

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

It has R stereochemistry

Highly water soluble

Acidic

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

Energy expanding system (sympathetic division of the PNS)

“Fight of flight”

Also has R stereochemistry

Also highly water soluble

Acidic

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

L-Tyrosine ⇒ *TYROSINE HYDROXYLASE* ⇒
L-DOPA ⇒ *DOPA DECARBOXYLASE* ⇒ Dopamine ⇒ *DOPAMINE B-HYDROXYLASE* ⇒ Norepinephrine ⇒ *N-METHYL TRANSFERASE* ⇒ Epinephrine

Metabolism
***Re-uptake (minor)
***Diffusion (minor)

1. COMP
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

The monoamine is taken away by oxidase

aka Aldehyde dehydrogenase

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

Binding affinity

Epinephrine ≥ Norepinephrine >>> Isoproterenol

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

*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

It is both in CNS and PNS
It is an amino acid decarboxylase

1. Dopamine-B-hydroxylase
2. MAO/ALDH (same as adrenergic hormones), and then catechol-O-methyltrransferase

Norepinephrine when using dopamine-B-hydroxylase

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

5 types; all GPCR

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

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

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

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

Nutrient accumulating systems (parasympathetic division of the PNS)

“Rest and digest”

Tryptophan ⇒ *TRYPTOPHAN HYDROXYLASE* ⇒ 5-Hydroxytryptophan ⇒ *AROMATIC AMINO ACID DECARBOXYLASE* ⇒ 5-HT

Re-uptake

1. MAO
2. ALDH

There are at least 14 different subtypes

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