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Different Benzodiazepines Mechanisms of Action

Therapeutic

Ex-Bluelighter
Joined
Sep 13, 2006
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Ok, well I thought this topic might be interesting as its never been discussed before.

Anyway, what I am trying to find out here, and hopefully here from some people that have pretty advanced knowledge in pharmacology, are the different mechanisms of action of different benzodiazepines. Yes, I know every benzo acts on GABA receptors, but I want to know more specifically which GABA receptors each one targets, or some benzo's that target a different GABA receptor more, and if any benzo's have any action on dopamine or serotonin as well.

Mainly interested right now in Alprazolam, Lorazepam, Clonazepam, Flunitrazepam, Diazepam, and Triazolam. If anyone could maybe post a description on the mechanisms of action of each of these and specifically which GABA receptors these target, that would be very interesting. I know that Lorazepam seems to target more GABA receptors than Diazepam does. I'd also like to know which ones.

Thanks to anyone that could contribute to this.
 
Beenhead said:
Im pretty sure most benzos are turned into Flurazepam in the liver. I would research the pharmacology of Flurazepam, I believe this would get you the answers you are looking for.

Are you sure?
Most benzos are metabolized into Oxazepam, that's sure, but Flurazepam??
 
jasoncrest said:
Are you sure?
Most benzos are metabolized into Oxazepam, that's sure, but Flurazepam??

Really?

I'm not saying you're bullshitting, but can you show me some evidence? I remember you showing me the diazepam breaking down into temazepam and oxazepam and I found that intresting! :)
 
All benzos and barbiturates and most other sedatives target the GABA-A chloride channels, just on different sites. Benzos all target the same area on the channel, the benzodiazepine site (clever name for it eh?).

Benzos don't even open the channel they just alter its conformation (shape) so that when GABA does bind the channel more Cl- is able to come in. The increased influx of Cl- into the neural cell makes it more difficult for the cell to to fire.

The reason why some benzos have varying actions can most likely be attributed to their pharmacokinetic properties, receptor affinity, physical properties (lipophilicity), etc.

This is the absolute basics but should be a good start.
 
Would it be correct to say that barbiturates have low affinity as a ligand (i.e., the can replace GABA at high concentrations and open the channel themselves) and benzos have virtually no affinity as a ligand, but the primary mode of action of each is to act as cofactors, albeit at different binding sites? This would explain the low therapeutic ratio of barbiturates compared to benzos.
On another note, which subreceptor is associated with the muscle relaxant properties of some benzos like clonazepam and diazepam, which are absent from other ones, like lorazepam?
 
hussness said:
Would it be correct to say that barbiturates have low affinity as a ligand (i.e., the can replace GABA at high concentrations and open the channel themselves) and benzos have virtually no affinity as a ligand, but the primary mode of action of each is to act as cofactors, albeit at different binding sites? This would explain the low therapeutic ratio of barbiturates compared to benzos.
On another note, which subreceptor is associated with the muscle relaxant properties of some benzos like clonazepam and diazepam, which are absent from other ones, like lorazepam?

The other thing I always have wondered about is lorazepam's slight Ambien-like effects on many people, including me. The proper dose will send text on my computer screen trickling away off the monitor in swarms. Utterly bizarre -- I wish someone would research this strange property a bit further.
 
GABA was never really my thing, so I'm not that hot on it, so this is really a starting point.

Benzos work by binding to the alpha and gamma subunits of the GABAa receptor.

Secondly I suspect that drugs which have 'rewarding' properties either stimulate the nucleus accumbens or inhibit the amygdala.

To my knowledge most downers give you a mellow feeling because your amygdala is less active.

There are three types of GABA receptors, a,b and c

GABA a are ligand gated ion channels

Under normal conditions GABAa receptors work a bit like 1 way valves, letting Cl- in but not letting it out. This makes the cell more negatively charged, hyperpolarising it and reducing neurotransmitter release.

GABAa receptors are structurally simliar to 5HT3 and nicotinic acetyl choline receptors, which are also ligand gated ion channels.

A GABAa receptor is made up of 5 separate polypeptide subunits and there have been seven (YES SEVEN!!) different subunit types identified. There is a variety of different viable subunit combinations possible, these all have different pharmacological properties. If I've read this right, then you need two gamma subunits and one alpha for benzos to bind, with different combinations of beta and alpha subunits affecting affinity (baring in mind there have been 6 alpha, 4 beta and 3 gamma subunits identified that gives you plenty of different permutations!!!!!)

GABA B and C are 'G protein coupled receptors' (GPCRs) and work by coupling to Gi, which work by blocking calcium channels and opening potassium channels, but may not be too important in the action of benzodiazepines.

Also, any mechanisms which promote release or inhibit reuptake (in the same way that MDMA promotes 5HT release) might also be important, as more GABA means more Cl- ion currents.
 
jasoncrest said:
Are you sure?
Most benzos are metabolized into Oxazepam, that's sure, but Flurazepam??

Gaz_hmmmm said:
Really?

I'm not saying you're bullshitting, but can you show me some evidence? I remember you showing me the diazepam breaking down into temazepam and oxazepam and I found that intresting! :)

http://www.norchemlab.com/reference/dtq/0103dtq02.htm

Well this is just one of the first search result when you search "benzodiazepines metabolized to oxazepam" on google, there are many other sources saying that many benzos are metabolized to oxazepam, it's the most common metabolites of benzodiazepines....
 
This topic has been discussed in detail in this thread. Go here for more info. In fact, I think maybe the two threads should be merged.

Matt the Raver said:
Benzos work by binding to the alpha and gamma subunits of the GABAa receptor.

Matt the Raver said:
If I've read this right, then you need two gamma subunits and one alpha for benzos to bind, with different combinations of beta and alpha subunits affecting affinity (baring in mind there have been 6 alpha, 4 beta and 3 gamma subunits identified that gives you plenty of different permutations!!!!!)

More specifically, benzodiazepines bind at the interface between a single gamma-2 and a single alpha-1,-2,-3, or -5 subunit. You do not need 2 gamma subunits for a benzo to bind.

Matt the Raver said:
Secondly I suspect that drugs which have 'rewarding' properties either stimulate the nucleus accumbens or inhibit the amygdala.

To my knowledge most downers give you a mellow feeling because your amygdala is less active.

I can't get into a detailed discussion of the systems mechanisms of drug action right now, but let's just say it's more complicated than the description above.

Matt the Raver said:
GABA a are ligand gated ion channels

Under normal conditions GABAa receptors work a bit like 1 way valves, letting Cl- in but not letting it out. This makes the cell more negatively charged, hyperpolarising it and reducing neurotransmitter release.

To clarify, the direction in which the cholride ions flow is determined primarily by the electrochemical driving force across the membrane, because the receptor protein can pass Cl- in either direction. Under normal conditions, when intracellular chloride levels are low, chloride flows inwards and therefore GABA is hyperpolarizing. However, under conditions where there is lots of GABAergic stimulation, the cell can become loaded with choride to the point where it reaches the reversal potential for chloride, which then flows out of the cell and thereby depolarizes it.

Matt the Raver said:
GABA B and C are 'G protein coupled receptors' (GPCRs)

Actually GABA C is an ion channel, not a GPCR.
 
5-HT2 said:
More specifically, benzodiazepines bind at the interface between a single gamma-2 and a single alpha-1,-2,-3, or -5 subunit. You do not need 2 gamma subunits for a benzo to bind.

I should point out that what I've posted is primarily based an internet search and a brief browse through a neuropharmacology book. I'm really not that hot at all on GABA. I know a bit on 5HT2A, a bit on 5HT1A and quite alot on 5HT2C, so thank you for straightening that out.

To be honest, I think the GABAa subunit thing needs a very detailed review, but that other thread is a very good starting point. Speaking of which, have you got any decent GABA reviews?

5-HT2 said:
I can't get into a detailed discussion of the systems mechanisms of drug action right now, but let's just say it's more complicated than the description above.

I'm sure it is more important than nucleus accumbens and amygdala, but again that's a starting point, I'll do a neurobiology thread on this at some point.

5-HT2 said:
To clarify, the direction in which the cholride ions flow is determined primarily by the electrochemical driving force across the membrane, because the receptor protein can pass Cl- in either direction. Under normal conditions, when intracellular chloride levels are low, chloride flows inwards and therefore GABA is hyperpolarizing. However, under conditions where there is lots of GABAergic stimulation, the cell can become loaded with choride to the point where it reaches the reversal potential for chloride, which then flows out of the cell and thereby depolarizes it.

I'm aware of the diffusion and electrochemical gradient, which dictates the flow of charged ions either in or out, but since we're talking about what happens normal conditions, I thought was a minor point. Anyway, is it actually possible reverse the chloride potential in healthy cells? If so, under what conditions?

5-HT2 said:
Actually GABA C is an ion channel, not a GPCR.

I'm sorry, that was a mistake on my part, like I said I'm kinda fuzzy on GABA
 
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