Propofol carbamate analog

FormerBeagle

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Any thoughts about this compound? I just noticed that 2,6-diisopropylphenol is available fairly inexpensively. The phenol itself has pretty problematic hurdles to recreational use, between the formulation issues, the difficulty in titrating a dose without full loss of consciousness, the necessity of IV administration, and the specter of death. So how about the carbamate? Works for other alcohols to give compounds with increased activity. Would be interesting to see if it was a prodrug only, or active as such. Also perhaps this would allow oral or intranasal, or vaporization as routes of admin. I think I've got some phosgene around here somewhere...
11820
 

FormerBeagle

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Yes, propofol did kill him. But my live-in anesthesiologist is more vigilant than his was.
 

Skorpio

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Wouldn't phosgene make a dicarbonate, or would the steric hindrance from the ortho Ips prevent that? If you can quench with ammonia quick enough it would probably fly, assuming that the phosgene could attack the alcohol at all.

Propofol and a shit ton of midazolam and other benzos and sleep meds killed mj. That being said hope your live in cardiologist knows cpr.
 

FormerBeagle

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Wouldn't phosgene make a dicarbonate, or would the steric hindrance from the ortho Ips prevent that? If you can quench with ammonia quick enough it would probably fly, assuming that the phosgene could attack the alcohol at all.
Phosgene is kind of the reagent to beat for this general reaction. I'm pretty sure it would attack the phenol, even with the steric hindrance. Might take some persuading though. Yes, ammonia would be step 2. There are probably better ways to get the carbamate in there these days, but what can I say? I'm a fan of the classics.

That being said hope your live in cardiologist knows cpr.
Are you kidding? He graduated from the top of his class at Hollywood Upstairs Medical College.
 

Skorpio

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I guess the other question is whether the carbamate would cleave in an appreciable amount to release an active dose, or if it would be active on it's own.

There is conflicting ish data on whether propofol binds the transmembrane helices as solvent anesthetics or closer to the pores as barbiturates do. If it binds at the transmembrane helices it may be less amenable to adding bulk than the barb region.
 

Skorpio

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Another thing to look into would be the kinetics of fospropofol, could be enlightening.
 

FormerBeagle

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I guess the other question is whether the carbamate would cleave in an appreciable amount to release an active dose, or if it would be active on it's own.
Yeah that is definitely one of the interesting topics at hand. The carbamate of placidyl for example is more potent than the parent, and the same holds true for simple alcohols (e.g. ethanol vs ethyl carbamate). But it is unclear to me if this is a pharmacokinetic effect (sneaking the drug past first-pass metabolism), or if the carbamates are active themselves.

here is conflicting ish data on whether propofol binds the transmembrane helices as solvent anesthetics or closer to the pores as barbiturates do. If it binds at the transmembrane helices it may be less amenable to adding bulk than the barb region.
Interesting. I've not really studied this aspect closely, but I think that barbiturates are allosteric modulators of GABA-A receptor, but I think that the volatile anesthetics do not need GABA to act. Not sure about propofol. I thought that the binding sites of propofol and barbiturates and benzodiazepines were all separate. I'm tempted to suspect that the binding site for propofol would be overlapping with an endogenous neurosteroid like the recently approved brexanolone (allopregnanolone).

nother thing to look into would be the kinetics of fospropofol, could be enlightening.
Pretty sure that fospropofol is propofol by the time it gets to the CNS.
 

Skorpio

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I was incorrect in my comment about propofol binding sites. It binds to both the barb and etomidate sites on GABA A. Linked is a paper that sums it up nicely.

 

FormerBeagle

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Interesting. I just assumed that they would be cleaved by esterase. Ethyl carbamate is hydrolyzed at the carbamate group at least to some extent. But looks like for the carbamates in methocarbamol and carisoprodol (and meprobamate) this is not a primary pathway. I really proposed this compound as a conversation starter more than anything. And didn't really think that I had any phosgene laying around anyway. Did just notice some triphosgene though. So perhaps if I get bored enough...
 
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