Ion Channels as Drug Targets Flashcards
What cells may ion channels be found in?
Excitable cells, eg neurons, cardiac myocytes, vascular smooth muscle and neuroendocrine cells
Non-excitable cells, eg lymphocytes, kidney and gut
Give four basic features of ligand-gated ion channels
They are ionotropic receptors
They are triggered to open by binding of a specific ligand such as 5-HT, NMDA, or ATP
They have a selectivity filter that discriminates between ions
They are classified based on size: trimers, tetramers and pentamers
Give some basic features of ion channels
They are integral, pore-forming, membrane proteins that allow ion flow according to electrochemical gradient.
What type of proteins are ion channels?
Integral, PORE-FORMING MEMBRANE proteins
What is the function of ion channels?
Allow ion flow according to electrochemical gradient
What type of EXCITABLE cells are ion channels found in? (list 4)
Neurons
Cardiac myocytes
Vascular smooth muscle
Neuroendocrine cells
What type of NON-EXCITABLE cells are ion channels found in? (list 3)
Lymphocytes
Kidney
Gut
What are the two main classes of ion channels?
1) ligand-gated
2) voltage-gated
Give the main features of a LIGAND-gated ion channel
IONOTROPIC receptors that are triggered to open by the binding of a SPECIFIC ligand
Give some examples of ligands that may trigger ligand-gated ion channels to open
5-HT
NMDA
ATP
What allows ion channels to discriminate between ions?
SELECTIVITY FILTER
Ion channels may be classified based on size. Which family are:
1) pentamers
2) tetramers
3) trimers
1) cys-loop receptor (nicotinic ACh) superfamily
2) glutamate receptor family
3) P2X receptor family
Give some examples of receptors in the Cys-loop receptor (nicotinic ACh) superfamily.
Nicotinic ACh receptor 5-HT3 receptor GABA(A) receptor Glycine receptor ZAC
What drugs are targeted against the following members of the Nicotinic Ach (cys-loop receptor) superfamily? What sort of ligand are each of these drugs?
1) 5-HT3
2) GABA(A)
3) Nicotinic
1) 5-HT3 - antagonist - alosteron
2) GABA - agonists - benzodiazepines (BZDs)
3) nicotinic - partial agonists - varenidine
Alosteron is a drug targeted against a specific type of ligand-gated ion channels. Which type?
The nicotinic ACh (cys-loop receptor) superfamily: it is an antagonist against 5-HT3 receptors
Which proteins do benzodiazepines target, and how?
GABA ion channels - they act as allosteric agonists
What drugs are targeted against members of the glutamate receptor family?
the NMDA receptor ANTAGONIST, memantine
No drugs are in clinical use for which ligand-gated ion channel family?
the P2X receptor family
Against which receptor is MEMANTINE targeted, and what is its clinical use?
It is an NMDA receptor ANTAGONIST, and is clinically used for Alzheimer’s disease
What are NMDA receptors?
1) members of the tetrameric glutamate receptor family
2) non-selective cation channels that allow calcium entry
How can Alzheimer’s disease be treated through targeting ligand-gated ion channels?
Excessive glutamate activity is neurotoxic in Alzheimer’s disease.
NMDA receptors are a member of the glutamate receptor family of ion channels; they are selective cation channels that allow calcium entry.
The NMDA receptor antagonist MEMANTINE can therefore be used to treat Alzheimer’s disease.
How can the activity of NMDA receptors be measured?
Whole-cell recording
What is MEMANTINE?
A non-competitive, low-affinity NMDA receptor antagonist
What is MEMNATINE’s clinical use?
An antineurotixic to combat excessive activity of glutamate receptors important in the pathology of Alzheimer’s disease
…slows the onset of symptoms
Calcium channels can be drug targets in which 3 main (general) areas?
1) cardiovascular system
2) chronic pain
3) epilepsy
Which type of calcium channels are involved in cardiac PHARMACOLOGY?
L-type calcium channels (aka dihydropyridine receptors)
What is another term for L-type calcium channels?
Dihydropyridine receptors
L-type calcium channels have the binding sites for dihydropyridines (DHPs). What is the nature of most dihydropyridines?
Most DHPs are calcium channel BLOCKERS, aka calcium antagonists (e.g. nifedipine)
Give an example of an L-type calcium channel blocker
Nifedipine (a dihydropyridine, DHP)
Calcium channels are present in both the heart and vascular smooth muscle. How are calcium channel blockers tissue-sensitive?
Dihydropyridines, DHPs (eg nifedipine) are NEUTRAL, and preferentially effective in vascular smooth muscle
Phenylalkylamines (eg verapamil) are CHARGED and are preferentially active in the heart
Which type of calcium blocker is preferentially active in vascular smooth muscle? Give an example
Dihydropyridines (DHPs), eg. nifedipine
…these are NEUTRAL
Which type of calcium blocker is preferentially effective in the heart? Give an example.
Phenylalkylamines, e.g. verapamil
…these are CHARGED
Phenylalkylamines (eg verapamil) can only bind to the calcium channel when it is in which state?
OPEN state
Dihydropyridines (eg nifedipine) are able to block calcium channels when they are in WHICH state(s)?
OPEN/ INACTIVATED states
How do Phenylalkylamines differ from Dihydropyridines in their binding to calcium channels?
Phenylalkylamines are charged drugs that only block calcium channels in their OPEN state. Therefore their blocking action is USE-DEPENDENT and the block is most effective in cell in which calcium channels are most active
What do Phenylalkylamines require in order to exert their effects? Therefore which cell type (and disorder) are they useful in treating?
The calcium channels to be in their open state, and an action potential.
CARDIAC MYOCYTES rapidly fire APs, therefore they are good targets for phenylalkylamines.
Used to treat CARDIAC DYSRHYTHMIAS
What can verapamil be used to treat?
Cardiac dysrhythmias
What is NIFEDIPINE, and what can it be used to treat?
A NEUTRAL drug (dihydropyridine) that binds channels in their open or inactive state, and impose a VOLTAGE-DEPENDENT BLOCK upon depolarisaton. As vascular smooth muscle tone is controlled by depolarisation, it is used for HYPERTENSION to relax smooth muscle of arterioles. Nifedipine will have some effects on the heart but preferential for the smooth muscle
What tissue does nifedipine act on?
Preferentially on the smooth muscle of arterioles (but has some effects on the heart)
How can calcium channels be targeted to treat chronic pain?
Analgesic drug based on w-connotoxin (ZICONOTIDE) blocks presynaptic N-type calcium channels in the dorsal horn to prevent release of nociceptive neuropeptides, eg substance P
What is ziconotide, and what is it used for?
An analgesic drug based on w-connotoxins that blocks presynaptic N-type calcium channels in the dorsal horn to inhibit release of nociceptive neuropeptides to treat CHRONIC NEUROPATHIC PAIN
How is ziconotide administered?
as an intrathecal injection
