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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
Q

What was wrong with the 1st thing tried when making sumatriptan? (5-CT)

A

Causes vasodilation and drop in BP.

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26
Q

What was right with the 1st thing tried when making sumatriptan? (5-CT)

A

Active against 5-HT1 and 5-HT2

27
Q

What was the 2nd thing tried when making sumatriptan?

A

Increase the length of the 5-CT by adding a methyl (CH2)

28
Q

Why did the add a methyl to the 5-CT (1st) to make the 2nd?

A

May have been some sort of hydrogen bonding taking place

29
Q

What was wrong with the 2nd thing tried when making sumatriptan? (5-CT with added CH2)

A

Inactive against 5-HT2 and causes vasodilation

30
Q

What was the 3rd thing tried when making sumatriptan?

A

Added a methyl to the terminal amide to the 2nd

31
Q

What was wrong with the 3rd thing tried when making sumatriptan?

A

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
Q

What was the 4th thing tried when making sumatriptan?

A

Changed the =O to a sulphonamide

33
Q

Why was 3rd thing tried when making sumatriptan changed my adding a sulphonamide (to make the 4th)?

A

Sulphonamides more stable

34
Q

What was wrong with the 4th thing tried when making sumatriptan?

A

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
Q

What was the 5th thing tried to finally make sumatriptan?

A

Added two methyl groups to the amine (NH2).

36
Q

Why were two methyl groups added to the 4th to make sumatriptan?

A

More metabolically stable as it will not go straight into phase 2 metabolism. Needs to take of methyls.

37
Q

What is the strongest interaction in sumatriptan binding?

A

The electrostatic bridge between the protonated amine and the aspartic acid unit. (salt bridge)

38
Q

What are the other interactions in sumatriptan binding?

A

3 H bonding

39
Q

What was ergotamine?

A

A vaso… used to treat migraine. Wanted to change to improve its travel though intercellular space between cells

40
Q

What happened when a large group associated with ergotamine was put onto serotonin (5-HT)? (1st)

A
  • Too hydrophilic for trans cellular absorption

- Too large to take advantage of para-cellular pore route

41
Q

What happened when a smaller group associated with ergotamine was put onto serotonin (5-HT)? (2nd)

A

-Got a partial agonist

42
Q

What happened when a smaller group associated with ergotamine was adjusted? (3rd)

A

Zolmitriptan

(The NH on the added ring changed to O)

43
Q

What chemical property will mean better passive diffusion through the BBB?

A

High clogP and logD.

44
Q

Zolmitriptan nasal bioavailability?

A

102% (low)

45
Q

Sumatriptan nasal bioavailability?

A

17% (low)

46
Q

What is sumatriptan metabolised by in the brain?

A

Monoamine oxidases

47
Q

What is Zolmitriptan (zoming) metabolised by in the brain

A

Cyp3A4

48
Q

How does sumatriptan become inactive when it is metabolised?

A

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
Q

How does Zolmitriptan (zoming) become inactive when it is metabolised? (longer half life)

A

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
Q

Zolmitriptan synthesis

A

Amine protection

51
Q

Fischer indole synthesis

A

Hydrazine and carbonyl type compound (ketone/aldehyde) to make an indole. (forms another ring)

52
Q

What is an alternative 5-HT1D agonist

A

Alniditan

53
Q

What is Alniditan?

A

Based on benzopyran structure rather than an indole.

54
Q

Alniditan synthesis (9)

A
  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
Q

What is CGRP?

A

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
Q

How does CGRP work?

A

Binds to CGRP receptor (heterotrimer), the receptor component protein causes signals to be sent, causing vasodilation.

57
Q

How does CGRP contribute to migraine?

A

Causing vasodilation, pulsing effect.

58
Q

How can you use CGRP to prevent migraine?

A

Inhibit CGRP or the receptor it binds to.

59
Q

What is a key site of action for CGRP?

A

Trigeminal ganglion

60
Q

Why can you make molecules that do not penetrate the BBB?

A

The trigeminal ganglion (where CGRP acts) is outside the BBB.

61
Q

Why is beneficial to have a drug that does not need to penetrate the BBB to be effective?

A

Can lower the clogP and logD to make it more orally available.

62
Q

How does sumatriptan act on CGRP?

A

Acts via presynaptic 5-HT1B/D receptors to suppress CGRP release from trigeminal nerves.

63
Q

The future with monoclonal antibodies and CGRP?

A

Monoclonal antibodies used to inhibit release and binding of CGRP and CGRP receptor.

Stage 3 Case 1 (12 decks)

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