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BS3054 > 5th Oct - Ion Channels as drug targets > Flashcards

5th Oct - Ion Channels as drug targets Flashcards

1
Q

How are ligand gated ion channels classified?

A

Based on size, so trimers, tetramers and pentamers

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2
Q

Give an example of a trimeric ionotropic receptor

A

P2X receptor

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3
Q

Give an example of a tetrameric ionotropic receptor

A

NMDA receptor
AMPA receptor
Kainate receptor

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4
Q

Give an example of a pentameric receptor

A

Nicotonic ACh receptor
Serotonin 3 receptor
GABA A receptor
Glycine receptor

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5
Q

Give an example of an NMDA receptor antagonist

A

Memantine used in alzheimer’s disease treatment

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6
Q

Why is memantine used in alzheimer’s disease treatment?

A

In AD there is excessive glutamate activity which leads to cell death, thus NMDA receptor blocking is neuroprotective. As memantine is a low-affinity antagonist it reduces side effects

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7
Q

Describe the structure of a VGCC

A

4 domains form an alpha 1 pore formin channel
Each domain has a pore forming region between the 5th and 6th TM helix
Each domain has a voltage sensor, the 4th TM helix
Each channel has a region important for activation, between domains III and IV
Several accessory subunits which can modulate function: alpha 2, delta, gamma and beta

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8
Q

Describe L-type calcium channels

A 
They have large conductance
Long lasting openings
Long lasting activation
Activation at larger depolarizations
High Voltage activated
Have a DHP binding site
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9
Q

Describe T-type calcium channels

A

Tiny conductance
Transient openings
Low voltage activated

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10
Q

What are the two chemically distinct classes of Ca2+ antagonist?

A

Phenylalkalines (charged) - effective in the heart and bind in the open state
Dihydropyridines (neutral) - effective in vascular smooth muscle and bind when in the open or inactivated state

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11
Q

What is verapamil?

A

A phenyalkaline which has strictly use dependent block on calcium channels, i.e. the block is more effective in those cells in which calcium channels are opening, thus an AP is required for it to function

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12
Q

What is verapamil used to treat?

A

Cardiac dysrhthymias

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13
Q

What is nifidepine?

A

A dihydropyridine which has use dependent and voltage dependent block on calcium channels, thus depolarisation is required for drug binding

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14
Q

What is nifidepine used to treat?

A

Hypertension to relax smooth muscle

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15
Q

What is ziconitide?

A

An analgesic based on omega conotoxins from the fish hunting cone snail. It blocks pre-synaptic n-type calcium channels in the dorsal horn of the spinal cord, inhibiting the release of nociceptive neuropeptides such as substance P.

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16
Q

What is the main clinical use of ziconitide?

A

Intrathecal injection to patients who are unresponsive to morphine with chronic or neuropathic pain

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17
Q

Name a drug that acts at the alpha2 delta subunit of a VGCC

A

Gabapentin

Pregabalin

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18
Q

What is the function of a drug that binds to the alpha2 delta subunit of the VGCC

A

Modulation of calcium influx and at synapses modulation of neurotransmitter release

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19
Q

Describe the structure of a local anaesthetic that targets a sodium channel

A

Aromatic region for diffusion through the sheath and lipid as it works on the intracellular region of the sodium channel

Ester/Amide bond

Channel binding via basic amine side chain

20
Q

Give an example of a local anaesthetic that targets sodium channels

A

Procaine

Lidocaine

21
Q

Outline the function of lidocaine

A

Local anaesthetic
-Blocks AP generation by blocking Na channels in their open or inactivated state in a use-dependent fashion , useful as a local nerve block

Class 1 Antidysrhythmic
-Blocks AP generation by blocking Na channels in their open or inactivated state in a use-dependent fashion, useful for tachycardia

22
Q

Name a sodium channel blocker used as an anti-epileptic

A

Phenytoin

Carbamazepine

23
Q

Why are phenytoin and carmazepine used to treat epilepsy?

A

Blocks AP tranisently in a use-dependent fashion thus stopping hyperexcitability

24
Q

What is a TRP channel?

A

Transient receptor potential channel

25
Q

What do TRP channels generally respond to?

A

Temperature, certain chemicals and osmolarity

26
Q

What does TRPV1 respond to?

A 
Heat
Botanical compounds
Protons
Proinflammatory agents
Voltage
Capsaicin
27
Q

Outline the structure of a TRP channel

A

6 TM segments
4X tetramers
Diverse cationic selectivites

28
Q

Where are TRPV1 channels expressed?

A

On nociceptors

29
Q

Name an antagonist of the TRPV1 channel

A

Capsazepine

30
Q

What is the clinical use of a TRPV1 antagonist?

A

Reverses pain behaviour in pain models

BUT side effect is hyperthermia

31
Q

What is the clinical use for a TRPV1 agonist?

A

Analgesia

32
Q

What is the side effect of using a TRPV1 agonist as an analgesic?

A

Hypothermia

33
Q

Name a TRPV1 agonist used clinically as an analgesic and what disease it is used for

A

Zacin - Osteoarthritis

Axsain - Diabetic neuropathy

34
Q

Why do we need to find new anti-epileptics?

A

About 1/3 of patients do not have satisfactory seizure control with existing drugs

35
Q

What is Ezogabine?

A

An anti-epileptic that is a neuronal K+ channel opener

36
Q

How does Ezogabine work?

A

It activates KCNQ channels stabilizing the resting membrane potential and reducing brain excitability

37
Q

What is the oldest type of potassium channel?

A

2 pore domain potassium channel

38
Q

Describe the structure of a 2 pore domain potassium channel

A

Each subunit has 2 pore domains so the functional channel is a dimer with a total of 4 pore domains

39
Q

What is responsible for the leaky potassium current?

A

The 2 pore potassium channel that controls membrane potential and excitability

40
Q

Is 2 pore domain potassium channel activation voltage dependent?

A

No

41
Q

What would be the clinical use of targeting a 2 pore domain potassium channel?

A

General anaesthetics target TREK1 and TASK1 on neurones causing hyperpolarisation and reduced excitability

42
Q

What’s ERG (Kv 11.1)?

A

Ether a go-go related channel important for repolarization of the cardiac action potential

43
Q

What can block of ERG cause?

A

Long QT syndrome

44
Q

What is Torsdes de pointes?

A

Is a rapid polymorphic ventricular tachycardia which involves twisting of the QRS complex of the ECG arouns the isoelectric point

45
Q

Why do so many drugs bind to ERG?

A

Large size of inner cavity
Aromatic residues
Polar residues

BS3054 (25 decks)

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