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Mutagenicity of carbamate sedatives

Synaps3

Synaps3

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Sep 14, 2011
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I am a chemist and I am interested in synthesizing some carbamate sedatives (possibly related to meprobamate, phenprobamate, etc.). The problem I'm facing is that I know about the mutegenicity of ethyl carbamate and vinyl carbamate (it's metabolite) and I can find plenty of research articles discussing it. However, what I can't seem to find is what exact changes in the molecule make something like meprobamate virtually non toxic and ethyl carbamate, very toxic. Based on my research, I've come to the conclusion that the mutagenicity of ethyl carbamate primarily has to do with its metabolite, vinyl carbamate. If you make sure the first carbon after the urea's oxygen is fully unsaturated (maybe that's not the right word; I mean all four bonds of the carbon are used), then when it gets metabolized it can't possibly vinylize.

That's my theory. I'd really appreciate some in depth information on this. It's the only thing that's preventing me from proceeding. Thanks.
 
First of all, it doesn't seem like ethyl carbamate is all that toxic. Secondly, you're on the right track to the most likely answer: meprobamate doesn't have a vicinal hydrogen relative to the -oxy group on the ethyl fragment. As such, it can't be dehydrogenated to yield an unsaturated compound (which in turn could be metabolized into an epoxide).

Just for clarification, unsaturation means the presence of carbon-carbon double or triple bonds. If you want to stress that a particular carbon has no hydrogens attached to it, you can say "quaternary carbon" which would be less confusing.
 
I once saw a paper where the anticonvulsant effectiveness of carbamates was compared and they found that phenethyl carbamate was most potent. Would phenethyl carbamate be metabolized to phenyl vinyl carbamate? Of course, if one is a legitimate chemist, one wouldn't have to synthetize that because it can be ordered from chemical suppliers.
 
polymath said:
I once saw a paper where the anticonvulsant effectiveness of carbamates was compared and they found that phenethyl carbamate was most potent. Would phenethyl carbamate be metabolized to phenyl vinyl carbamate? Of course, if one is a legitimate chemist, one wouldn't have to synthetize that because it can be ordered from chemical suppliers.
Click to expand...

I think it would be metabolized to that. Would that be mutagenic? And btw, I'm not a legitimate chemist :) I am just doing this as a fun experiment/learning process.
 
Synaps3 said:
Good, that confirms what I thought.

I want to be 100% sure on this though because I do plan on testing some compounds on myself. The simplest carbamate I would most likely be interested in making is 2-methyl-2-butanyl carbamate. Should I be worried about the ethyl part of the molecule somehow vinylizing.

Here is a diagram of ethyl carbamate metabolism:
http://www.ec.gc.ca/ese-ees/C24225A8-22AE-4AF9-9292-9E04B48D615F/ch2.jpg

Could this happen?
http://oi64.tinypic.com/210mzhy.jpg
Click to expand...

Doubt it. I'm not a pharmacologist, just a chemist, but something tells me that the dehydrogenation relies on the presence of the carbamoyloxy group, so it won't occur (at least not so well) farther from it. But don't take my word for it, and I wouldn't really take anyone's word for it without some empirical proof if it's a new compound. I don't recommend testing that on yourself, especially if you're not an experienced chemist, because you may leave reagents and other impurities in the end product, which of course will hardly be of any help.
 
If you are not 150% sure of the identitiy fo the compounds you're making and their toxicology, don't consume them.

Do you want to be like the guy who gave himself Parkinsons from badly cooked MPPP?
 
The patent of meprobramate cites other patents & papers where just about all of the alkyl analogues are dealt with.
 
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