So - it is possible to produce 1,5-benzodiazepines as potent as the 1,4-benzodiazepines

[Fertile]

3

Image 3 hosted in ImgBB

ibb.co

After messing around datamining, I used Chemsketch to draw and generate SMILES format of some potent (and patented) 1,5-benzodiazepines.

Now, many if not most are actually prodrugs to slow onset and possible allow a steady level of the active (epilepsy and anxiety treatments) to flow around the patients system.

3-methyl derivatives have also been patented although I am the first to admit that although all of the halides, pseudohalides and nitro groups are found at the appropriate position but nobody has patented a 1,5-benzodiazepine alcohol mimic. Well, as things go, that's good news. So I can manipulate the 1,4 & 1,5 elements so that their relative potency and duration will be appropriate.

Even Professor James T. Cook hasn't got this far.

 

[Fertile]

US-RE30293-E - 3-ring
US-4111934-A- 4-ring

You may notice that the 2-keto is missing. This is the prodrug. Many well researched clobazam relatives also lack this ketone but the body easily converts it to the ketone. There is much data on the topic.

So it remains to be seen JUST how strong a 1,5-benzodiazepine (especially one with a triazolo ring) can be made. If it's possible to produce a dose-unit with decent activity with less than 1mg of material.

Of course, pynazolam required 20-30mg but replacing the 2-pyridyl with a '2-F should increase potency by a factor of about 6 and if I do my sums right, I can produce an alcohol-free drink that means 0.25-0.5mg of the dimer will act like a stiff double.

After all, alcohol kills 2.6 million people per annum and that does not include accidents and violent crime (over 60% of which are carried out by people who are drunk).

But of course, the key is producing a dimer that binds the 3-OH derivatives via a butane-1,4-diol bridge. Why go for 1 compound rather than 2? Because if I use 2 novel compounds, BOTH have to go through the array of tests required for foods & drinks (hoping to avoid it actually being classed as a drug).

So it takes time and effort.

Of course, all the details I do not mention. Like MAKING a potent 1,5benzodiazepine. From the point of view of someone seeking to produce an RC, it's knowing an appropriate (commercially available) starting-point so that the product is only 2 steps away (for a 4-ring example). It will be interesting to see if someone tries.

 

[Fertile]

BTW Professor James T. Cook at Minneapolis University School of Medicine is the Shulgin or Nichols of the benzo world. A name to look for.

qh

Image qh hosted in ImgBB

ibb.co

Above is the very first drug designed as a probe for the effects of alcohol. It is detailed in WO-03082832-A2. The 7-ethynyl stops all a2 & a3 affiinity affinity. The problem is like my efforts. half a dose does nothing, double up and you end up drunk in 10 minutes.

sch

Image sch hosted in ImgBB

ibb.co

So then Cook introduced a triazolo ring which precludes a1 affinity and so the ONLY GABA subreceptor that the compound will bind to is the a5 and is it like ethanol? YES, it's JUST like alcohol except for the fast onset and long duration and slow decline. Still, 15mg gets you elephant's trunk,

tf

Image tf hosted in ImgBB

ibb.co

Finally cook adds a '2F which increases potency by a factor of 5. Onset even faster, duration even longer, decline SLOW. Take on Friday night and you MAY make it out by Sunday afternoon.

But we independently proved that all of the negative effects of alcohol (amnesia, emotional lability, aggression, loss of executive control) are ALL mediated by a1 affinity (alcohol binds to a1 & a5). But a5 selective compounds also FEEL great. https://ibb.co/XsKcfbL details it all.

BUT there is a problem - the fact that half a dose does nothing while 2 half doses leaves you asleep on the couch. My belief is that the a5 subunits of the b2 & b3 GABA receptors, although mild when taken alone, combine to produce a good, safe dose-response curve and so I need a 1,5-benzodiazepine.

15

Image 15 hosted in ImgBB

ibb.co

So here is the 1,5 homologue of the first compound Cook produced. EP-1925614-A1

Now having coresponded with professor Cook (a friend of Nutt- enough said?) I know he also produced the '2F derivative (x5 parent in potency) and the triazolo with '2F (some 15 x parent) which would be convenient since then a 2-bottle of wine level of trollied to the bladder, hammered, blasted, blitzed and mullered to the can in just 10 short minutes with the level of intoxication lasting 4-5 hours and then returns to abstemious state in another 4-5 makes it a highly enjoyable drug - one that 95% of adults are familiar with but few realize that a hangover is not a sure thing.Yes, you do enjoy your breakfast, but no dehydration, no illness, shakes, seizures or all of those bad things.

But presuming that 1mg of the dimer equals 1 UK unit of alcohol (10 mL of 100% ethanol) would mean that tax and duty would need to be agreed upon and adopted, licencing laws would need to be updates and the emergency services would need to recognise and appropriately react to an overdose. After all, be it ethanol or an ethanol mimic, do you want a driver on either to be using the road near you.

Then import and export, licencing of chemical designs and many, many other aspects would need to be dealt with.

Of course, one way is to simply put the stuff out there and let's see how the police control supply and distribution of something almost EVERY alcohol drinker would much prefer?

 

[Delmonte421]

Even Professor James T. Cook hasn't got this far.

James Cook - Milwaukee Institute for Drug Discovery

Distinguished Professor Emeritus of Chemistry and Biochemistry Education BS in Chemistry with Honors, West Virginia University Ph.D in Organic Chemistry, University of Michigan Positions Held Laboratory Technician, Fikes Chemicals, Nitro, W. Va., l964‑1965 Supervisor of Research Laboratory and...

uwm.edu

 

[fastandbulbous]

Just keeps bringing up weird mental images. James Cook was the explorer who brought knowledge of Australia to European awareness, or Prof. James T. Cook, captain Kirk's clever cousin!?

Sorry, just stood out as James Cook is a big part of our history in N. E. England (was even the name of the hospital that carried out my cardiac surgery, so I'd pass my M.O.T .)

I'll behave myself, now.

PS. On a serious note: isn't part of the bigger picture, the NMDA antagonism it provides? That's part of the whole psychopharmacology of ethanol

 

[Fertile]

Yes - his email address begins captaincook@......

A bit of a dick actually, one of those people who are annoyed when someone points out their mistakes (in a polite manner). He missed a stack of prodrugs in his patents, so I helpfully pointed out the holes. He barely contained his anger, maybe because he assumed I would tell Nutt that he wasn't THAT smart.... but Nutt is the same, so I wouldn't bother.

Nichols is a MUCH nicer guy.

 

[fastandbulbous]

I know Dave Nichol's chief synthetic chemist, when he was at Perdue uni. He is a really nice bloke and it just harks back to my bits about even the rrsearchers connected to psychedelic research are basically people with a much more pleasant demeanor...

 

[Fertile]

What, the hippie dude? Yeah, he's lovely. But then consider his commute every morning 'I'm going to make drugs -LEGALLY!'

Better than Nutt & Cook who will put their name on ANYTHING because they like to read their own reviews (Nutt really did have a pile of his own reviews).

I like being the unknown quantity. Nichols took my aminorex work.... and while pleased, was concerned for me. I like that he cares.