Calcium Channel Blockers and Ion Transporters Flashcards
What type of calcium channels do CCB target?
L-Type channels
Summarise the structure of an alpha-1 subunit
24 transmembrane domain
6 alpha helix repeating units (4x6)
What are the functional parts of a domain?
1) Subunit 4 = Voltage sensor
2) Subunit 5-6 = P selectivity filter
What is the effect of membrane depolarisation?
Subunit 4 (voltage sensor) rotates towards extracellular side and undergoes conformational change = opened
What causes membrane depolarisation?
1) Action potential
2) Graded potential
What does increased calcium concentration lead to?
1) Increased skeletal contraction
2) Inotropy - cardiac contraction
3) Increased smooth muscle contraction
What makes up a 1-4 dihydropyridine?
1) Aldehyde
2) Beta-ketoester
Summarise the key medicinal chemistry components of a CCB to enhance activity
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
What decreases the activity of a CCB med chem
1) Nitro substituent in turn of an ester - as activator
2) Alteration of amine
3) substituent on substituted benzene being in the para position
What can increase activity of a CCB med chem?
1) Increase length of hydrophobic chains
What enzymes are responsible for the metabolism of CCB?
P450 enzymes metabolise by oxidation and decrease reactivity
Why does calcium have a higher rate of transport through the channel?
Has a 2+ charge
Faster than 1+
What type of receptors do L-Type calcium channels have?
Dihydropyridine receptors
What are the 3 classes of CCB?
1) Dihydropyridines
2) Phenylalkylamines
3) Benzothiazapines
What class of CCB is best for hypertension?
Dihydropyridines
What CaV channels are associated with the heart and blood vessels?
1) 1.2
2) 1.3
Where are the dihydropyridine receptors located?
On the extracellular membrane of the alpha 1 subunit
How does the P450 enzyme make dihydropyridines inactive?
Turns the dihydropyridine ring into a pyridine ring, eliminating the amine
What ions can pass through a potassium channel?
1) Potassium
2) Rubidium
How many water molecules hydrates potassium?
6
How many water must potassium lose to bind to the ion channels?
4
What does potassium bind to in the ion channels?
Coordinate bonds with the carbonyl groups that come from amino acid residues = most stable
Give a summary of what happens in a potassium channel
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
Why wont Na+ pass through a K+ channel?
Smaller and less energetically stable
Only forms 2 coordinate bonds in channel instead of 4
More stable outside channel = favourable
What ions can pass thrugh a sodium channel?
