5th Oct - Ion Channels as drug targets Flashcards
How are ligand gated ion channels classified?
Based on size, so trimers, tetramers and pentamers
Give an example of a trimeric ionotropic receptor
P2X receptor
Give an example of a tetrameric ionotropic receptor
NMDA receptor
AMPA receptor
Kainate receptor
Give an example of a pentameric receptor
Nicotonic ACh receptor
Serotonin 3 receptor
GABA A receptor
Glycine receptor
Give an example of an NMDA receptor antagonist
Memantine used in alzheimer’s disease treatment
Why is memantine used in alzheimer’s disease treatment?
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
Describe the structure of a VGCC
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
Describe L-type calcium channels
They have large conductance Long lasting openings Long lasting activation Activation at larger depolarizations High Voltage activated Have a DHP binding site
Describe T-type calcium channels
Tiny conductance
Transient openings
Low voltage activated
What are the two chemically distinct classes of Ca2+ antagonist?
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
What is verapamil?
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
What is verapamil used to treat?
Cardiac dysrhthymias
What is nifidepine?
A dihydropyridine which has use dependent and voltage dependent block on calcium channels, thus depolarisation is required for drug binding
What is nifidepine used to treat?
Hypertension to relax smooth muscle
What is ziconitide?
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.
What is the main clinical use of ziconitide?
Intrathecal injection to patients who are unresponsive to morphine with chronic or neuropathic pain
Name a drug that acts at the alpha2 delta subunit of a VGCC
Gabapentin
Pregabalin
What is the function of a drug that binds to the alpha2 delta subunit of the VGCC
Modulation of calcium influx and at synapses modulation of neurotransmitter release
Describe the structure of a local anaesthetic that targets a sodium channel
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
Give an example of a local anaesthetic that targets sodium channels
Procaine
Lidocaine
Outline the function of lidocaine
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
Name a sodium channel blocker used as an anti-epileptic
Phenytoin
Carbamazepine
Why are phenytoin and carmazepine used to treat epilepsy?
Blocks AP tranisently in a use-dependent fashion thus stopping hyperexcitability
What is a TRP channel?
Transient receptor potential channel
What do TRP channels generally respond to?
Temperature, certain chemicals and osmolarity
What does TRPV1 respond to?
Heat Botanical compounds Protons Proinflammatory agents Voltage Capsaicin
Outline the structure of a TRP channel
6 TM segments
4X tetramers
Diverse cationic selectivites
Where are TRPV1 channels expressed?
On nociceptors
Name an antagonist of the TRPV1 channel
Capsazepine
What is the clinical use of a TRPV1 antagonist?
Reverses pain behaviour in pain models
BUT side effect is hyperthermia
What is the clinical use for a TRPV1 agonist?
Analgesia
What is the side effect of using a TRPV1 agonist as an analgesic?
Hypothermia
Name a TRPV1 agonist used clinically as an analgesic and what disease it is used for
Zacin - Osteoarthritis
Axsain - Diabetic neuropathy
Why do we need to find new anti-epileptics?
About 1/3 of patients do not have satisfactory seizure control with existing drugs
What is Ezogabine?
An anti-epileptic that is a neuronal K+ channel opener
How does Ezogabine work?
It activates KCNQ channels stabilizing the resting membrane potential and reducing brain excitability
What is the oldest type of potassium channel?
2 pore domain potassium channel
Describe the structure of a 2 pore domain potassium channel
Each subunit has 2 pore domains so the functional channel is a dimer with a total of 4 pore domains
What is responsible for the leaky potassium current?
The 2 pore potassium channel that controls membrane potential and excitability
Is 2 pore domain potassium channel activation voltage dependent?
No
What would be the clinical use of targeting a 2 pore domain potassium channel?
General anaesthetics target TREK1 and TASK1 on neurones causing hyperpolarisation and reduced excitability
What’s ERG (Kv 11.1)?
Ether a go-go related channel important for repolarization of the cardiac action potential
What can block of ERG cause?
Long QT syndrome
What is Torsdes de pointes?
Is a rapid polymorphic ventricular tachycardia which involves twisting of the QRS complex of the ECG arouns the isoelectric point
Why do so many drugs bind to ERG?
Large size of inner cavity
Aromatic residues
Polar residues
