Ion channels pharmacology Flashcards
What are the domains of an ion channel and what drugs target them
Sensor - agonist/antagonist
Gating - allosteric modulator
Selectivity filter - pore blocker
Historical examples of ion channel naming methods
Named after the selective ligands that identified the specific ion channel species.
E.g., nAChRs, mAChRs
NMDA, AMPA, kainate
Different responses were observed for kainic acid and NMDA.
Subunit selectivity and influence on competitive antagonists
Ion channels are made up of a combination of different subunits.
Antagonists (and agonists) can target specific ion channel subunits. Therefore the combination (ratio) of the different subunit compositions of the ion channel influences the efficacy of the subunit-specific antagonist.
E.g., UBP-210 is selective for GluK2 subunits. Will be most effective in a GluK2 homotetramer, whereas less effective in heteromers, or completely ineffective in GluK1 homotetramers.
AMPA receptor allosteric modulator and its effects on ion flow kinetics
Cyclothiazide.
Has no direct effect upon binding, but significantly slows ion channel desensitisation.
Causes a shift in EC50.
Increased total inwards current flow through the pore. It stays open for longer.
Example of pore blockers and their mechanism
Memantine, LAs.
Memantine blocks NMDA receptor pores. It is use-dependent - the channel must activate for the antagonist to be able to then occupy the pore binding site.
It is a voltage-dependent block.
Lidocaine is a VGSC blocker. Blocks propagation of APs in sensory neurons.
What influences the druggability potential for an ion channel
NMDA receptors are significantly more complex than AMPA receptors with a lot more potential binding sites, such as polyamine, ZN2+ and phosphorylation modulatory sites. Also has an Mg2+ block.
Glycine and d-serine co-transmitter sites also are present.
The large number of modulatory sites means that the ion channel has a large number of potential drug targets.
NMDA antagonism - excitotoxicity and LTP
Cell cultures containing neurons and glioma together saw tumour-induced excitotoxicity. When NMDAR antagonists were added, they had a neuroprotective effect, reducing the excitotoxicity.
Theta-burst stimulation (TBS) was seen to cause LTP and STP (short-term potentiation). When NMDA antagonist D-AP5 was used, there was decreased LTP and STP. Shows the endogenous role of NMDA in LTP and STP of hippocampal cells.
Varenicline
A selective partial agonist for neuronal nAChR. Used to stop smoking, but also seen to be effective for alcohol and drug dependence.
The mechanism for smoking cessation is reducing the effect of nicotine through competition for nAChR.
Also seen to decrease DA release, which would reduce the addictive potential of other co-administered drugs. Specific MOA unclear.
Diazepam
Sedative and muscle relaxant. Anxiolytic.
A PAM for GABAA. Binds to the benzodiazapine allosteric binding site which is found at the gamma-alpha subunits interface.
Enhances endogenous GABA neurotransmission.
Examples of ion channel poisons and toxins and their MOA
Strychnine - glycine and nAChR antagonist.
conotoxin
tetrodotoxin (VGSC blocker)
Scorpion toxins, spider toxins, and frog toxins (frog toxins mostly peptides)
