Fundamental and practical differences between high and low potency benzodiazepines

[Kdem]

Although I've been doing a little research, I didn't get very far.

In the past, low potency benzodiazepines were more commonly prescribed.

What I get, is that in general low potency benzodiazepines are more sedating. The 'high potency' benzodiazepines are sort of a 'second generation' of benzodiazepines ?
What would be the mechanism of this different effect ?

I do have that impression that it has something to do with binding with a certain (selective) affinity for GABAA subunits, something I discussed in another thread. I haven't been able to get much information about that subject.

 

[adder]

I didn't find such a relationship between potency and properties, benzodiazepines of higher potency weren't really synthesized at a later time either. Different effects indeed derive from different activity at different subunits. Benzodiazepines with higher affinity at alpha-1 and alpha-5 subunits are generally more hypnotic and amnesic while those with higher affinity at alpha-2 and alpha-3 are generally more anxiolytic, but it's a very simple way of differentiating between 1,4-benzodiazepine-sensitive subunits, for instance anti-convulsant effects are mediated through alpha-1 and alpha-3. There is a nice thread on this subject here. There are no alpha-5 ligands named there, if I remember correctly, lorazepam is one being active mainly at alpha-1 and alpha-5.

 

[Kdem]

Valium and Librium came first, right ?
Regardless of when they were synthesized, the high potency benzos were introduced at a later time.
Alprazolam came onto the market in the 1980s and 1990s, right ? And this is a reference to sales volume, not when they were made available for sale for the first time.
Clonazepam, while synthesized a long time ago, was mass marketed in the USA in the 1980s or 1990s ?

I'm familiar with the thread, it's a lot like the tripsit.wiki. If not identical. I must say I have my doubts about some of that 'information'. Does diazepam really have a high alpha2 and 3 affinity ?

 

[adder]

I don't know the dates of introduction of specific benzodiazepines, so my post didn't really concern that. Chlordiazepoxide was the first benzodiazepine to be synthesized, diazepam followed, and what happened later in respect to specific derivatives, I don't really know. As it happens with every promising new class of drugs, I'm sure more and more derivatives were synthesized in search of drugs more specific for anxiety, insomnia, and convulsions. Alprazolam came around a decade later or so, I suppose estazolam was synthesized at the same time and while they're very similar, estazolam is considerably more hypnotic, but if you insisted, you could call triazolobenzodiazepines a second generation, I guess. Anyway, I guess it's still hard to draw a conclusion that more potent benzodiazepines are less sedative.

I'm not really sure about the data on benzodiazepines binding to specific subunits presented in the other thread and where it came from, but the descriptions of effects mediated through different subunits are about right. I've found the article mentioned there: link. According to the article diazepam is a pretty balanced alpha-1/2/3/5 agonist. I didn't read the whole article yet, perhaps there is some supplementary information not included in the file with more tables.

 

[Kdem]

Thank you for that.

Unfortunately, drugs such as clonazepam and lorazepam are not discussed.
Diazepam seems to be 'balanced'.

However, I suspect that alpazolam and clonazepam have a higher relative affinity for the alpha 2 and alpha 3 subunit.