Sciencemadness Discussion Board

Ro15-4513 an anti-drunk drug?

Ritter - 18-7-2008 at 09:51

When Roche accidentally discovered the benzodiazepine family of tranquilizer drugs, they undertook a massive development program to exploit the various CNS effects produced by these drugs. For instance, flurazepam was launched because it caused sleep. Alprazolam (Xanax), developed at Upjohn, is specific to anxiety.

One agent had an unexpected effect: it turned absolurely stone drunk lab rats into sober & alert lab brats. Previously, alcohol intoxication had been considered a general depression. Now the Roche researchers had proof that alcohol had a receptor-mediated effect, acting on the benzodiazepine receptors (which are related to GABA receptors). Ro15-4513 was classified as an inverse agonist.

Roche never commercialized this drug due to ethical & liability concerns. It would be useful in emergency room settings where physicians neede to communicate with intoxicated accident victims. But there was too much concern about it getting diverted to become a 'party drug.'

[Edited on 18-7-2008 by Ritter]

Ro15-4513.gif - 6kB

JohnWW - 18-7-2008 at 14:14

Which stereoisomer (probably diastereoisomer) is it? Both of the Ns in the 7-membered ring are optically active (chiral).

Sauron - 18-7-2008 at 16:20

At least one of those nitrogens, with a Me group, can readily invert. Most likely both of them. Cycloheptyl rings are not known for rigidity or planarity.

Ritter - 18-7-2008 at 17:11

Quote:
Originally posted by JohnWW
Which stereoisomer (probably diastereoisomer) is it? Both of the Ns in the 7-membered ring are optically active (chiral).


I have no information on that.

DJF90 - 18-7-2008 at 17:59

So how do we synthesise it? Any info to start on?

not_important - 18-7-2008 at 21:42

Interesting is the side effect of causing convulsions if the dose is too high, as well as increased tremor in animals already subject to them. This suggests that delirium tremens is a result of downregulated receptors failing to respond to normal GABA levels in the absence of alcohol intake.

Ritter - 19-7-2008 at 08:38

Quote:
Originally posted by DJF90
So how do we synthesise it? Any info to start on?


I came up empty of a Google search for a patent reference but I did find that it was patented in 1984. The closest I could get was this patent http://www.pat2pdf.org/patents/pat4489003.pdf.

Roche has lots of patents on preparing 'imidazobenzodiazepines,' so finding the best route would be a major research job as the best routes are not always shown in Composition of Matter patents. For reference, most of these patents are in Class 540/494.

sparkgap - 30-7-2008 at 11:55

Interesting... it looks just a tad like flumazenil. Mazicon is pretty good for reversing benzodiazepine intoxication; I suspect the bulkiness in the right places (and the electron-withdrawing azido group too) are contributory to antagonist activity.

I'm just speculating, though. I've worked with drugs bu was never really much for neuropharmacology.

sparky (~_~)

Ritter - 1-8-2008 at 12:02

Quote:
Originally posted by sparkgap
Interesting... it looks just a tad like flumazenil. Mazicon is pretty good for reversing benzodiazepine intoxication; I suspect the bulkiness in the right places (and the electron-withdrawing azido group too) are contributory to antagonist activity.


sparky (~_~)


I think the 2 drugs were developed at about the same time. Fluamazenil is Ro 15-1788, not too far from Ro 15-4513. Like most pharma companies, their internal compound code numbers were issued more or less sequentially.

sparkgap - 2-8-2008 at 09:15

If such is the case, I won't be surprised. The azido group, among other things, is often used to replace halogen groups (F- among them; bioisosteric is the term of art) when medicinal chemists are tweaking group this and substituent that in evaluating the pharmacological activity of a series of congeners.

sparky (~_~)

Ritter - 2-8-2008 at 09:41

The benzodiazepines have an amazing range of effects. One of my favorites is the anterograde amnesia produced by midazolam (Versed). I asked for it before recent eye surgery & don't remember a thing!

Midazolam.gif - 17kB

sparkgap - 2-8-2008 at 09:50

I would in fact extrapolate that the imidazolo- and triazolobenzodiazepine series are much richer with regards to the variety of effects congeners of this series can give to the human brain than the traditional ones.

sparky (~_~)