Ligand gated ion channels 2 Flashcards
What are some drugs that target GABAa receptors?
Benzodiazepines, alcohol, barbiturates, anaesthetics, neurosteroids.
What are the actions of benzodiazepines?
Anxiety relieving, anticonvulsant.
What are the two types of modulation that allosteric modulators can cause?
Positive modulators (enhance agonist induced action) and negative modulators (reduce agonist-induced action).
How do allosteric modulators exert their effects of GABAa receptors?
Some benzodiazepines increase GABA induced Cl- channel opening by increasing the efficacy of GABA for the channel opening by increasing the open frequency probability, whereas some decrease GABA induced Cl- channel opening.
Why are allosteric modulators beneficial as LGIC drug targets rather than antagonists?
Binding isn’t restricted to the ligand-binding site/ion pore, orthosteric antagonists block the receptor and obliterate the physiological response, positive modulators can turn up an inhibitory pathway and negative can reduce agonist sensitivity and activity.
What is one of the key benefits of allosteric modulators compared to antagonists?
They can target particular receptor subtypes depending on the subunit composition.
Where are the binding sites for GABA on GABAa receptors?
There are two at the interface between the alpha/beta subunits.
Where do benzodiazepines bind?
The interface between the alpha/gamma subunit.
What is the structure of benzodiazepines?
The core is a benzene ring joined to a 7-membered, 1,4-diazepine ring.
What is the impact of the R side groups on benzodiazepines?
They influence the affinity of the BZ to bind to the receptor and intrinsic efficacy to produce a functional effect.
What is the intrinsic efficacy of benzodiazepines?
100%.
What do benzodiazepine inverse agonists do?
Bind to the site but produce the opposite effect and are said to have negative intrinsic efficacy.
Where do benzodiazepine antagonists bind?
The alpha/gamma site - they cannot activate the receptor (0% intrinsic efficacy).
What are the five different classes of benzodiazepines?
Agonists, partial agonists, competitive antagonists, partial inverse agonists, inverse agonists.
What are the therapeutically beneficial effects of benzodiazepines?
Sedation, anxiolysis, hypnotic, anticonvulsant.
What are the negative effects of benzodiazepines?
Memory loss, sedation, abuse potential, addictive, withdrawal syndrome.
What GABAa receptors bind benzodiazepines?
Receptors containing combinations of alpha, beta and gamma2 subunits.
What alpha subunits must be expressed in order for benzodiazepines to bind?
Alpha2, alpha3, alpha3 and alpha5 containing receptors.
Does the type of beta subunit effect benzodiazepine binding to GABA receptors?
No - it has no effect on binding.
What effect does changing a His to Arg residue in the BZ binding site have?
It prevented the binding of classical BZs, but doesn’t affect receptor assembly or sensitivity to GABA>
What alpha residues contain His and which contain Arg?
A1/2/3/5 contain His and a4/6 contain Arg residue.
What are the sedative and amnesic effects of diazepam mediated by?
GABAa receptors that contain alpha1 subunits.
What are the anxiolytic effects of diazepam mediated by?
GABAa receptors that contain alpha2/3 subunits.
What is Zolpidem?
A hypnotic that isn’t a benzodiazepine but acts at the same site.
What are the actions of Zolpidem?
It is a positive allosteric modulator at the BZ site that potentiates the effects of GABA.
What happens if there is a point mutation in the gamma2 subunit of Zolpidem?
It’s sensitivity is removed electrophysiologically and behaviourally.
What could be beneficial about identifying alcohol actions at specific GABAa receptor subtypes?
Developing: alcohol antidotes (reversal of intoxication), alcohol addiction treatments (remove pleasurable effects of alcohol), alcohol mimetics (beneficial effects of low dose alcohol).
What are the CNS effects of alcohol?
It is a CNS depressant, the stimulatory effects result from depression of inhibitory control mechanisms in the brain, euphoria, impaired thought processes, decreased mechanical efficiency.
What relationship do the effects of alcohol have with the dose?
Dose-dependent relationship.
What can benzodiazepines be used to treat?
The effects of abrupt alcohol withdrawal (seizure).
What GABAa receptors are sensitive to ethanol?
Alpha4/6, beta and gamma containing GABAa receptors.
What is Ro-15-4513?
An alcohol antagonist.
What receptors does Ro-15-4513 bind to?
It has high affinity for alpha4/6, beta, delta containing receptors.
