The effects of adding specific elements or groups to benzos

[bupropion]

What are the ways that adding certain elements or groups of elements affects their strength or desirability, or gives them specific unusual qualities?

For instance:

Stronger, more euphoric (with possible exception of #4):

1) Triazolo ring
2) Nitro (N20) group
3) Fluorine on further phenyl
4) Chlorine on further phenyl

Unusual effects:

Triazolo ring - dissociation (according to a medical book)
Cl on further phenyl - suicidality (PDR on Ativan) - but this doesn't hold with Clonopin


What else?

Are Halcion and Rohypnol the only ones with 2 of the above properties?

And would a CF3 have a greater effect than a single fluorine?

What about the effect of the (typical) oxygen attached to the diazepine ring, and the ones with a second oxygen?

Maybe the chlorine on the closer ring is depressing as well (?). I haven't tried one that doesn't have it.

And has a benzo with #1, 2 and 3 ever been made?


Edit: Quazepam has some unusual stuff on it. Has anyone tried it?

 

[Ham-milton]

what do you mean by 'further phenyl'- there's only one phenyl group on benzos.

Your language is really hard to follow with some of these. What the hell are you talking about here: "What about the effect of the (typical) oxygen attached to the diazepine ring, and the ones with a second oxygen?"

Are you talking about the ketone? I've never seen one with two ketones, but I have seen some with a hydroxy group. You need to figure out what you're asking and then use language we can understand.

Better yet- because all of this can easily be found on your own, why don't you go through and look it up yourself?

 

[haribo1]

Making the amide function tertiary seems to be one guaranteed way of making it more euphoric. I won't list every one, but nitrazepam to nimetazepam, the second being much more euphoric. A triazolo ring is an example as well as an -N substituant.

Substitution at the 7 position changes things. Nitro seems to mean hypnotic, Chloro or Bromo anxiolytic.

Substitution of the '2 position increases potency. Fluoro>Chloro.

Examples with a 3 substitution would be -OH (like oxazepam) or COO- like chlorazepate. But, I guess that a 3 methyl would be interesting because then you end up with 2 isomers...

I could go on, but suffice to say that using what is known about all of the benzodiazipines currently or previously used gives a very good SAR. It's about the clearest example of a a versatile skeleton that one could hope for.

Oh, and of course, putting an ethylene group on the 7 position makes a drug that acts on the GABA receptors like alcohol. I bet that the '2 fluoro version of that would be a lot of fun...

 

[rockbottom]

alcohol s your best bet or grapefruit juice if your a sissy

 

[Ham-milton]

Haribo1, do you know if nitro has been tried at the 2' carbon? I can't think of any, but since halogens are almost always located there, and the nitro group subs for a halo at the 7 carbon, it might do well here?

 

[SpellmanT7]

Better yet- because all of this can easily be found on your own, why don't you go through and look it up yourself?

Ham - would you be prepared to agree, that based on haribos posting, it was possible to provide a more constructive response than your initial reply in this thread?

I see your point in regards to the OP's lack of understanding but haribo seemed to interpret the shortfall in knowledge and attempt to clarify matters somewhat.

 

[Ham-milton]

Ham - would you be prepared to agree, that based on haribos posting, it was possible to provide a more constructive response than your initial reply in this thread?

I see your point in regards to the OP's lack of understanding but haribo seemed to interpret the shortfall in knowledge and attempt to clarify matters somewhat.

No, I don't think it has anything to do with a lack of understanding, I see it as a lack of effort. All of this information is easily available through wikipedia (structures), and after going through all of those structures you can ask informed questions.

And if the language used to ask questions is wrong, it needs to be very specific. I don't have the proper terms for everything I want to describe, so I make sure to use as specific language as possible-ie: "what about the effect of the (typical) oxygen attached to the diazepine ring"- is this talking about a hydroxy group or a ketone? If you don't know that the double bonded oxygen is called a ketone, you can at least refer to it as a double bonded oxygen. There are often hydroxy groups on these, and there's (almost) always a ketone. No one can answer much with it described as it was above.

And if he was referring to the ketone- then removing it will make the drug inactive. Replacing it with a hydroxy group will probably do the same, but will definitely decrease the potency. Only replacing it with a triazolo ring will allow for similar potency and/or activity. Of all the gabaergic depressants, only one that I can think of (Pipequaline) is active without a keto, triazolo or hydroxy. Though for all I know it could be a prodrug. I don't have any papers on it.

 

[mad_scientist]

And if he was referring to the ketone- then removing it will make the drug inactive. Replacing it with a hydroxy group will probably do the same, but will definitely decrease the potency. Only replacing it with a triazolo ring will allow for similar potency and/or activity.

Medazepam and fletazepam are both active even though the 2-ketone group is not present.

http://en.wikipedia.org/wiki/Medazepam

http://en.wikipedia.org/wiki/Fletazepam

and quazepam is active even though =O has been replaced by =S

http://en.wikipedia.org/wiki/Quazepam

 

[Ham-milton]

according to my 1995 book medazepam is just a pro-drug for diazepam. I can't can't find anything updating that though. I would assume fletazepam is also a prodrug for desfluoro-halazepam.

It also looks like Quazepam may be a prodrug for a flurazepam derivative. I can't find anything to confirm or deny that. It's 6am here, so I'm gonna go back to bed.

 

[haribo1]

Haribo1, do you know if nitro has been tried at the 2' carbon? I can't think of any, but since halogens are almost always located there, and the nitro group subs for a halo at the 7 carbon, it might do well here?

Not been tried, or if it was, it didn't get very far. Cl,F & -N= at the '2 position is the only ones that have surfaced.

Those lacking the 2 =O seem to be oxidised. The same happens to chlorodiazepoxide. 2 =S is there because the =S is quite easy for the body to oxidise. Other benzos have S in it's 2 oxidation state for the same reason. The triazolo ring was one of THE breakthroughs in the chemistry of this class. I would bet that the triazolo analog of flunitrazepam would be a hefty sedatine...

 

[Ham-milton]

Do you know if clomethiazole is oxidised as well? Looking at all of the other GABAergics out there, there are a few with odd sulfur groups, if they are oxidised as well, it might make for unscheduled active drugs- bypassing the prodrug. Not that scheduling matters for clomethiazole.

It's very interesting that the triazolo ring can substitute for a ketone at the receptor protein. They don't have much in common, but it doesn't seem to affect the receptor preferences either.

I wonder if there's possibly some natural substance with such a ring that binds there. I don't understand why the receptor would have developed to accept such a different functional group.

 

[Jamshyd]

Etizolam was FAR more euphoric than other benzos I have tried.

Notice whats different about it?

 

[rave23]

I see your point in regards to the OP's lack of understanding but haribo seemed to interpret the shortfall in knowledge and attempt to clarify matters somewhat.

That's why i love reading his posts. Always good interpretation and lots of sources.

Does anybody know how the size / weight of the molecule affects the properties of the benzodiazepine? Are there any corelations?

 

[bupropion]

Clarification

What are the ways that adding certain elements or groups of elements affects their strength or desirability, or gives them specific unusual qualities?

For instance:

Stronger, more euphoric (with possible exception of #4):

1) Triazolo ring
2) Nitro (N20) group
3) Fluorine on further phenyl
4) Chlorine on further phenyl

Unusual effects:

Triazolo ring - dissociation (according to a medical book)
Cl on further phenyl - suicidality (PDR on Ativan) - but this doesn't hold with Clonopin


What else?

Are Halcion and Rohypnol the only ones with 2 of the above properties?

And would a CF3 have a greater effect than a single fluorine?

What about the effect of the (typical) oxygen attached to the diazepine ring, and the ones with a second oxygen?

Maybe the chlorine on the closer ring is depressing as well (?). I haven't tried one that doesn't have it.

And has a benzo with #1, 2 and 3 ever been made?


Edit: Quazepam has some unusual stuff on it. Has anyone tried it?

What are the ways that adding certain elements or groups of elements affects their strength or desirability, or gives them specific unusual qualities?

For instance:

Stronger, more euphoric (with possible exception of #4):

1) Triazolo ring
2) Nitro (N20) group
3) Fluorine on ring C
4) Chlorine on ring C

Unusual effects:

Triazolo ring - dissociation (according to a medical book)
Triazolo ring - less sedation? (just a (probably incorrect) guess)
Cl on Ring C - suicidality (PDR on Ativan) - but this probably isn't a general rule and just applies to Ativan


What else?

Are Halcion and Rohypnol the only ones with 2 of the above properties?

And would a CF3 have a greater effect than a single fluorine?

What about the effect of the ketone on ring B,
the hydroxyl some have on ring B,
and the 2 ketones on ring B that some 1,5 benzodiazepines have?
(I think I saw a benzo without the ketone or a triazolo ring but I guess it may be a prodrug)

Maybe the chlorine on Ring A is depressing as well (?). I haven't tried one that doesn't have it.

And has a benzo with #1, 2 and 3 ever been made?

 

[vecktor]

No, I don't think it has anything to do with a lack of understanding, I see it as a lack of effort. All of this information is easily available through wikipedia (structures), and after going through all of those structures you can ask informed questions.

And if the language used to ask questions is wrong, it needs to be very specific. I don't have the proper terms for everything I want to describe, so I make sure to use as specific language as possible-ie: "what about the effect of the (typical) oxygen attached to the diazepine ring"- is this talking about a hydroxy group or a ketone? If you don't know that the double bonded oxygen is called a ketone, you can at least refer to it as a double bonded oxygen. There are often hydroxy groups on these, and there's (almost) always a ketone. No one can answer much with it described as it was above.

yah, hate that too, people should get their terminology right, it just shows lack of effort. For example when when people refer to a lactam carbonyl as a ketone. 8)
Also it is really annoying when people confuse allosteric ligands with othosteric ligands and so make the elementary error of thinking that the endogenous ligand for the BZP site is GABA.

People should get everything correct and know everything before they post a question, but then again If one knows everything and never makes a mistake then there is no purpose in asking any questions at all.

 

[Jamshyd]

I think I posted the structure of Etizolam like 3 times now on ADD, no one one seems to notice.

This chunk with sulphur on it (I don't know what you call it) seems to add a fundamental change to the benzo's nature - I read some studies that seem to suggest an effect on NE whch might explain the immediate mood-lift experienced with such a benzo.

 

[immaturepoop]

its called thiophene, but are the thienobenzodiazepines usually more euphoric from experience? I've haven't tried any of them, but how would you compare it to the more common benzos or even hypnotics Jamshyd?

 

[Ham-milton]

yah, hate that too, people should get their terminology right, it just shows lack of effort. For example when when people refer to a lactam carbonyl as a ketone. 8)
Also it is really annoying when people confuse allosteric ligands with othosteric ligands and so make the elementary error of thinking that the endogenous ligand for the BZP site is GABA.

People should get everything correct and know everything before they post a question, but then again If one knows everything and never makes a mistake then there is no purpose in asking any questions at all.

Apparently you didn't take the time to read what I had written or you'd realize you just made my point for me. If the language isn't right, it needs to be clear enough to figure out what is meant. You seem to have managed that fine here, huh?

(oh, and I said that GABA is binding at BZP receptors?)

 

[johanneschimpo]

^ Apparently you don't understand sarcasm...

 

[kokaino]

johann,

are you going to close this thread because "thread going nowhere, no HR value" ?
Might aswell close about 90% of the threads then, because typically people like to discuss things on forums and not try to make a "thread go somewhere".