Calcium Channel Blockers and Ion Transporters

Question 1

What type of calcium channels do CCB target?

Answer 1

L-Type channels

Question 2

Summarise the structure of an alpha-1 subunit

Answer 2

24 transmembrane domain
6 alpha helix repeating units (4x6)

Question 3

What are the functional parts of a domain?

Answer 3

1) Subunit 4 = Voltage sensor
2) Subunit 5-6 = P selectivity filter

Question 4

What is the effect of membrane depolarisation?

Answer 4

Subunit 4 (voltage sensor) rotates towards extracellular side and undergoes conformational change = opened

Question 5

What causes membrane depolarisation?

Answer 5

1) Action potential
2) Graded potential

Question 6

What does increased calcium concentration lead to?

Answer 6

1) Increased skeletal contraction
2) Inotropy - cardiac contraction
3) Increased smooth muscle contraction

Question 7

What makes up a 1-4 dihydropyridine?

Answer 7

1) Aldehyde
2) Beta-ketoester

Question 8

Summarise the key medicinal chemistry components of a CCB to enhance activity

Answer 8

1) Benzene substituent on para carbon
2) Substituent on ortho or meta carbon of the benzene substituent - introduces steric lock
3) 2 ester substituents on ring
4) Amine - H- bond acceptor

Question 9

What decreases the activity of a CCB med chem

Answer 9

1) Nitro substituent in turn of an ester - as activator
2) Alteration of amine
3) substituent on substituted benzene being in the para position

Question 10

What can increase activity of a CCB med chem?

Answer 10

1) Increase length of hydrophobic chains

Question 11

What enzymes are responsible for the metabolism of CCB?

Answer 11

P450 enzymes metabolise by oxidation and decrease reactivity

Question 12

Why does calcium have a higher rate of transport through the channel?

Answer 12

Has a 2+ charge
Faster than 1+

Question 13

What type of receptors do L-Type calcium channels have?

Answer 13

Dihydropyridine receptors

Question 14

What are the 3 classes of CCB?

Answer 14

1) Dihydropyridines
2) Phenylalkylamines
3) Benzothiazapines

Question 15

What class of CCB is best for hypertension?

Answer 15

Dihydropyridines

Question 16

What CaV channels are associated with the heart and blood vessels?

Answer 16

1) 1.2
2) 1.3

Question 17

Where are the dihydropyridine receptors located?

Answer 17

On the extracellular membrane of the alpha 1 subunit

Question 18

How does the P450 enzyme make dihydropyridines inactive?

Answer 18

Turns the dihydropyridine ring into a pyridine ring, eliminating the amine

Question 19

What ions can pass through a potassium channel?

Answer 19

1) Potassium
2) Rubidium

Question 20

How many water molecules hydrates potassium?

Answer 20

6

Question 21

How many water must potassium lose to bind to the ion channels?

Answer 21

4

Question 22

What does potassium bind to in the ion channels?

Answer 22

Coordinate bonds with the carbonyl groups that come from amino acid residues = most stable

Question 23

Give a summary of what happens in a potassium channel

Answer 23

1) K+ loses 4 water molecules
2) K+ binds to 4 carbonyls in first loop
3) K+ passes through to second loop
4) =ve charges from 2 K+ repel = ion passes through

Question 24

Why wont Na+ pass through a K+ channel?

Answer 24

Smaller and less energetically stable
Only forms 2 coordinate bonds in channel instead of 4
More stable outside channel = favourable

Question 25

What ions can pass thrugh a sodium channel?