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Stage 3 Case 1 > Migraine chemistry > Flashcards

Migraine chemistry Flashcards

1
Q

What is serotonin?

A

Monoamine neurotransmitter

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2
Q

Serotonin chemical name

A

5-hydroxytrypamine (5-HT)

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3
Q

What receptor does serotonin have activity on?

A

5-HT receptors

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4
Q

Biosynthesis of serotonin

A

Simple enzymatic hydroxylation and decarboxylation process

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5
Q

Which amino acid is serotonin synthesised from?

A

Tryptophan

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6
Q

What is Serotonin (5-HT) amide from in the body?

A

From the amino acid tryptophan

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7
Q

How is serotonin made from tryptophan?

A

Two step process. Simple enzymatic hydroxylation and decarboxylation process

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8
Q

How is tryptophan made into 5-hydroxylrytophan (5-HTP)? (1st step serotonin synthesis)

A

Hydroxylation

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9
Q

How is 5-hydroxylrytophan (5-HTP) made into serotonin?

A

Aromatic amino acid decarboxylation.

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10
Q

What is serotonin a precursor of?

A

Melatonin (serotonin has been acetylated)

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11
Q

How is serotonin metabolised within the body?

A

Monoamine oxides from the brain can oxidise the amine to an OH (5-hydroxytryptophol) or allow the to a COOH (5-Hyrdroxyindole-3-actetic acid)

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12
Q

How many 5-HT receptors?

A

7

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13
Q

Triptan main receptor target?

A

5HT1D (expressed widely in the CNS)

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14
Q

Triptan other receptor targets?

A

5HT1F and h-5HT1B

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15
Q

Triptans act as…

A

Agonists at 5HT1 (5HT1D, 5HT1F and h-5HT1B)

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16
Q

Agonist

A

Chemical that binds to a receptor and causes it to elicit a specific response. A neurotransmitter like 5HT/serotonin is an endogenous agonist

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17
Q

Antagonist

A

Chemical that binds to a receptor and blocks the response of that receptor

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18
Q

Partial agonist

A

Bind to the receptor but only elicit a partial response, even at maximal occupancy

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19
Q

Inverse agonist

A

Binds to the same receptors as an agonist and gives a pharmacological response that as inverse to the antagonist.

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20
Q

What is the general structure of triptans?

A

Similar to serotonin (5-HT), modification to 5-hydroxyl and amine.

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21
Q

Why would you want to change the NH2 on triptans?

A

As NH2 is metabolised straight to phase 2 so changing will prevent metabolism.

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22
Q

What physicochemical properties affects BBB penetration?

A

LogP and LogD

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23
Q

What 3 things does change the amine and 5-hydroxyl have on the drug?

A

Physical properties, CNS penetration and LogP

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24
Q

What was the 1st thing tried when making sumatriptan?

A

Extended the 5-hydroyl group to a terminal amide (5-carboxamidotryptamine (5-CT))

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25
What was wrong with the 1st thing tried when making sumatriptan? (5-CT)
Causes vasodilation and drop in BP.
26
What was right with the 1st thing tried when making sumatriptan? (5-CT)
Active against 5-HT1 and 5-HT2
27
What was the 2nd thing tried when making sumatriptan?
Increase the length of the 5-CT by adding a methyl (CH2)
28
Why did the add a methyl to the 5-CT (1st) to make the 2nd?
May have been some sort of hydrogen bonding taking place
29
What was wrong with the 2nd thing tried when making sumatriptan? (5-CT with added CH2)
Inactive against 5-HT2 and causes vasodilation
30
What was the 3rd thing tried when making sumatriptan?
Added a methyl to the terminal amide to the 2nd
31
What was wrong with the 3rd thing tried when making sumatriptan?
Not orally bioavailable as putting the amide in acid will cause it to hydrolyse which will make charged zwitterions that are hard to uptake into the intestines.
32
What was the 4th thing tried when making sumatriptan?
Changed the =O to a sulphonamide
33
Why was 3rd thing tried when making sumatriptan changed my adding a sulphonamide (to make the 4th)?
Sulphonamides more stable
34
What was wrong with the 4th thing tried when making sumatriptan?
Acidic sulphonamide and basic amine can react. The H from the sulphonamide can jump to the amine to form a zwitterion (charged) – molecule overall neutral
35
What was the 5th thing tried to finally make sumatriptan?
Added two methyl groups to the amine (NH2).
36
Why were two methyl groups added to the 4th to make sumatriptan?
More metabolically stable as it will not go straight into phase 2 metabolism. Needs to take of methyls.
37
What is the strongest interaction in sumatriptan binding?
The electrostatic bridge between the protonated amine and the aspartic acid unit. (salt bridge)
38
What are the other interactions in sumatriptan binding?
3 H bonding
39
What was ergotamine?
A vaso… used to treat migraine. Wanted to change to improve its travel though intercellular space between cells
40
What happened when a large group associated with ergotamine was put onto serotonin (5-HT)? (1st)
- Too hydrophilic for trans cellular absorption | - Too large to take advantage of para-cellular pore route
41
What happened when a smaller group associated with ergotamine was put onto serotonin (5-HT)? (2nd)
-Got a partial agonist
42
What happened when a smaller group associated with ergotamine was adjusted? (3rd)
Zolmitriptan | (The NH on the added ring changed to O)
43
What chemical property will mean better passive diffusion through the BBB?
High clogP and logD.
44
Zolmitriptan nasal bioavailability?
102% (low)
45
Sumatriptan nasal bioavailability?
17% (low)
46
What is sumatriptan metabolised by in the brain?
Monoamine oxidases
47
What is Zolmitriptan (zoming) metabolised by in the brain
Cyp3A4
48
How does sumatriptan become inactive when it is metabolised?
It goes straight to acid as the H bonding and electrostatic salt bridge has been changed. (N with two methyl becomes =O and OH)
49
How does Zolmitriptan (zoming) become inactive when it is metabolised? (longer half life)
First goes through mono de methylation so still active as it can form the salt bridge. Then goes to acid where it is inactive.
50
Zolmitriptan synthesis
Amine protection
51
Fischer indole synthesis
Hydrazine and carbonyl type compound (ketone/aldehyde) to make an indole. (forms another ring)
52
What is an alternative 5-HT1D agonist
Alniditan
53
What is Alniditan?
Based on benzopyran structure rather than an indole.
54
Alniditan synthesis (9)
1. Alkylation 2. Oxidation 3. Cyclysation 4. Reduction (taking off carbonyl) 5. Reducation (to aldehyde) 6. Amination 7. Alkylation 8. Deprotection of the benzyl 9. Alkylation
55
What is CGRP?
37-amino acid neuropeptide derived from the gene encoding calcitonin. Functions as a messenger in nerve cell and as a vasodilator. High CGRP is associated with migraines.
56
How does CGRP work?
Binds to CGRP receptor (heterotrimer), the receptor component protein causes signals to be sent, causing vasodilation.
57
How does CGRP contribute to migraine?
Causing vasodilation, pulsing effect.
58
How can you use CGRP to prevent migraine?
Inhibit CGRP or the receptor it binds to.
59
What is a key site of action for CGRP?
Trigeminal ganglion
60
Why can you make molecules that do not penetrate the BBB?
The trigeminal ganglion (where CGRP acts) is outside the BBB.
61
Why is beneficial to have a drug that does not need to penetrate the BBB to be effective?
Can lower the clogP and logD to make it more orally available.
62
How does sumatriptan act on CGRP?
Acts via presynaptic 5-HT1B/D receptors to suppress CGRP release from trigeminal nerves.
63
The future with monoclonal antibodies and CGRP?
Monoclonal antibodies used to inhibit release and binding of CGRP and CGRP receptor.

Stage 3 Case 1 (12 decks)

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