Ritter
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Ro15-4513 an anti-drunk drug?
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]
Ritter
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Karl Marx
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JohnWW
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Which stereoisomer (probably diastereoisomer) is it? Both of the Ns in the 7-membered ring are optically active (chiral).
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Sauron
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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.
Sic gorgeamus a los subjectatus nunc.
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Ritter
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| 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.
Ritter
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\"The production of too many useful things results in too many useless people.\"
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DJF90
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So how do we synthesise it? Any info to start on?
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not_important
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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.
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Ritter
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| 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.
Ritter
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\"The production of too many useful things results in too many useless people.\"
Karl Marx
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sparkgap
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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 (~_~)
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Ritter
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| 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.
Ritter
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\"The production of too many useful things results in too many useless people.\"
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sparkgap
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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 (~_~)
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Ritter
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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!
Ritter
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\"The production of too many useful things results in too many useless people.\"
Karl Marx
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sparkgap
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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 (~_~)
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