QSAR of the Quinazolones Sedatives

[clubcard]

Since the discovery of the sedative/hypnotic effects of methaqualone by Dr M. L. Gujiral in 1950, it seems that the only systematic work on the QSAR seems to have been a series of German articles in 'Journal für Praktische Chemie' in 1961. The discovery of methaqualone uncovered an interesting pattern:

Nitromethaqualone (x4 methaqualone)

Methanitroqualone (x5 methaqualone)

This compound interested me. A nice EWG without the dangers of forming a mutogen.

Trifluoromethaqualone?

So it would seem that a strong EWG is required either ortho or para to the basic amine. We also know that potency may be doubled by the addition of an -F

What is interesting is that the -Cl analogue was totally inactive.

Substitution of the other benzene has been tried in every position, especially by the Japanese, but none of these compounds came to anything.


I wondered if others HAVE come across a QSAR and if one doesn't exist, are there enough people here with enough papers to produce a good QSAR?

If you have access to Reaxys, it seems like Klosa made 100s of analogues. Pity my German sucks. Chemspider DOES find a lot of analogues and it's always been my rule-of-thumb
that if the makers took the trouble and expense to get a CAS assigned, they must, on balance, thought it may have SOME use.

You see, I was amazed that after dimethaqualone and bromoqualone, whoever was behind the flow of analogues went for etaqualone which is much weaker. 2-methyl-3-chloro being
50% stronger as it is...

Thoughts anyone?

 

[clubcard]

US Patent 1076747

I notice that many of these analogues have a 7-NH2... so safety is a question.

 

[DL-ark]

Can someone look into Apigenin with this? I know it isn't a quinazolone but it has a similar structure and a fairly similar pharmacology.

 

[clubcard]

a)No human studies
b)May have been cause the damage to the red cells.

I agree that is one are I haven't studied much because a long time ago, I was told by someone far more expert than me and there seems like there are stacks everywhere. I haven't got it, but can someone who has it tell if Shulgin's last book covered all of this class?

 

[clubcard]

OK - one interesting substitution (that appears to increase potency) is the addition of a 7 -NH2. You may have seen the dozen or so patents on this modification. Interesting that etifoxine overlays methaqualone very well, it's just that second benzene that is off.

 

[sekio]

Apigenin and the other flavones are pretty much next to worthless as drugs, they are heavily metabolized in the liver & have erratic bioavailibility.

 

[DL-ark]

Apigenin and the other flavones are pretty much next to worthless as drugs, they are heavily metabolized in the liver & have erratic bioavailibility.

True, however, apigenin is said to be more active than most flavones. It is funny how much flavones resemble GABA PAMS but unfortunately they lack the strength and activity to become such drugs.

 

[sekio]

With a BA of ~0.2%, somehow I doubt it. It's still only active in the micromolar range (1000s of nanomoles).

It hits lots of targets though, it's by no means selective for GABA, it also interferes with protien kinases and adenosine receptors and acetylcholinesterase, CYP liver enzymes, and others. [ref]

 

[DL-ark]

^ Really? that low? Holy moly you were right then, however Apigenin, as you said inhibits several CYP enzymes so could it potentially increase it's own bioavailability?

Also, where is the source for the BA number, not doubting it but I am curious.

 

[sekio]

Oopsy. Here. It's the BA from consuming 2 grams of parsely.
http://www.ncbi.nlm.nih.gov/pubmed/16407641

 

[DL-ark]

Interesting, obviously we know that parsley isnt particularly active but is it possible that apigenin in parsely is less available than pure or extracted apigenin? Eg it is in some sort of hard to digest plant cells or proteins? Anyway me thinks apigenin is derailing this thread...

 

[clubcard]

I note that 7-OH & 7-NH2- is widely patented for newer lude analogues. Interesting that at roughly the same point on benzos, an EWG is favoured but 7 -NH2 or -OH are BIG in the patents. An aromatic amine to add to methaqualone. i think WITH THE STRONG nitromethaqualones, nobody has looked properly if a TFM group would work.... or at least non of my sources pop one out....

 

[Synaps3]

I've been interested in the similarities between methaqualone and apigenin. My knowledge of pharmacology is pretty limited, but what about looking at some of the aspects of apigenin and adding them to a quinazolone. You mentioned adding OH or NH2 to position 7 increased potency, so why not try adding the two OHs like apigenin or add a phenyl to the upper methyl (sorry I don't understand the positions so I have to describe).

Something like this:

 

[SONN]

my bad for not searching apigenin before making the new thread. Isn't it quite possible that making a tea out of it would have made it significantly more bioavailable? I'm using pure fresh chamomile from egypt,(not prepackaged and heavily processed 'chamomile tea' you can get from the supermarket) and brewing tea out of at least 5 grams of it or so.