Benzodiazepines without Halogens?

[Soulfake]

Has anyone heard of Benzodiazepines without halogens and/or with added methoxy or methyl groups (or something else) instead?
I wonder why every Benzodiazepine I have seen so far has some kind of halogen attached, would the potency in any other case be too small? I almost can´t imagine that there is no substitution that would make an effective compound, even if you would have to take more of it like 100mg instead of 1-10. Especially the triazolo´s could be potent enough to be effective with the halogens replaced by methyl or methoxy units? I would be especially interested how a methoxy unit would change the effects as it would create a more "natural" looking compound. Are there at least some that have only 1 halogen and 1 methyl/methoxy or other substitution?


(The picture only shows some drawings I made)

 

[d1nach]

Why? My guess is it would make it weaker because diethyl either is a example of ether bond being replaced by halogenated compounds which are used today for anesthesia. Also in generally most new drugs have the addition of a chloro fluoro or bromo an example of this is flonase via a fluorine and 25i mmobe albiet which almost killed me replacing methoxy groups on the mescaline trimethoxybenzeneketocarboxylic acid backbone with bromo

 

[Soulfake]

Why? My guess is it would make it weaker because diethyl either is a example of ether bond being replaced by halogenated compounds which are used today for anesthesia. Also in generally most new drugs have the addition of a chloro fluoro or bromo an example of this is flonase via a fluorine and 25i mmobe albiet which almost killed me replacing methoxy groups on the mescaline trimethoxybenzeneketocarboxylic acid backbone with bromo

Of cause there seems to be a reason why they use halogenated compounds but I could imagine that halogens could be responsible for the (disputed, some studies claim it while others say it s not the case) toxicity of Benzos in terms of the cancer-promoting effects of long-term use for example. Also it would look more "natural" if there would be a different substitution and maybe also "feel" more natural, at least that´s my experience with many compounds (for example Amphetamine -> 4-fluoro Amphetamine / non halogenated Opioids vs. halogenated ones (Tilidine, Codeine, Oxycodone vs Ah7291, U47700, Fluoro-Fentanyl or also synthetic cannabinoids like JWH250, JWH081, CP-47,497 vs. almost all halogenated ones (5-fluoropentyl´s))

 

[d1nach]

I see what your saying here but i think there are equally as many examples where unnatural subsitutions to chemicals make them safer and less toxic for example scopolamine methylbromide the addition of a halogen here reduces its toxicity by decreasing its ability to enter the cns where as with natural scopolamine for motion sickness or vomiting your likely to experience hallucinations and other unplesant effects.

I think given such a critical role gaba plays in the brain any benzo will cause issues long term rather than it being a result of toxic byproducts ect.

 

[serotonin2A]

Your post is based on a fundamental misunderstanding of chemistry and pharmacology. There is nothing "unnatural" or inherently bad about drugs containing halogen atoms. Our bodies contain many halogens atoms (sodium chloride, triiodothyronine, etc).

Of cause there seems to be a reason why they use halogenated compounds but I could imagine that halogens could be responsible for the (disputed, some studies claim it while others say it s not the case) toxicity of Benzos in terms of the cancer-promoting effects of long-term use for example. Also it would look more "natural" if there would be a different substitution and maybe also "feel" more natural, at least that´s my experience with many compounds (for example Amphetamine -> 4-fluoro Amphetamine / non halogenated Opioids vs. halogenated ones (Tilidine, Codeine, Oxycodone vs Ah7291, U47700, Fluoro-Fentanyl or also synthetic cannabinoids like JWH250, JWH081, CP-47,497 vs. almost all halogenated ones (5-fluoropentyl´s))

There is no way for the brain to sense whether a drug molecule contains a halogen versus some other substituent -- the "feelings" you are experiencing have nothing to do with the presence of halogens in those drugs. 4-F-amphetamine has different pharmacological properties compared to amphetamine; the fluorine itself is not what causes the different subjective sensation, but rather because the fluorine substitution alters the selectivity of the drug for different monoamine transporters.

 

[d1nach]

I could be wrong but i get the impresion that soulflake is coming from a more observation and reasoning way of looking of things based on his dharmacharkara user image. While your user name is refering to the 5 hydroxytryptamine 2a receptor so are likely more heavily influenced by hardcore science way of seeing things.

Therefore, someone who sees halogens tend to make things more toxic and natural compounds in their experience ie pot opium green tea tendnto be less toxic compared to fentanyl.

Would logically conclude halogens make things more toxic .

I agree that the pharmacology not halogen itself contributes tp the toxicity and halogens arent unatural but i can see how someone could come to that conclusion


Btw soulflake did you makenthat change to the halogen group to a methoxy group on a computer program if so thats pretty sweet

 

[d1nach]

G0to sorry sometimes i talk in chemistry nonsense.

Methoxy is just you see on the where you see ---o--- on the picture

What i meaant it looks like he took ---cl (chlorine is a halogen) off a known compound and replaced with a ----o---- to make his picture

 

[white55]

like this?

 

[d1nach]

Thats interesting having nitrogen in so many places compaeed to alprazolam is this a used drug in humans?

 

[white55]

No, it's a potential improvement on https://en.wikipedia.org/wiki/Zolazepam

 

[skytouching]

I'm curious if this is strictly based on chem or personally I'd be curious of the chem/ pharmacological correlations?

 

[Weltmeister]

Theres probably a paper or patent with these compounds floating around somewhere. I cant think of a reason why pfizer/roche/whatever wouldnt have tried these substitutions already

 

[Solipsis]

Nitrazepam and nimetazepam are halogen-free
Methoxy ethers are probably not electron-withdrawing enough? I guess it makes for weak and metabolizable shit

But I don't think nitrazepam feels more natural or something like that, if halogen subsistutions play a role in feelings from various drugs you find 'unnatural' it is from correlation at best and not causation if you ask me.

I do find it curious how unrelated drugs can feel like they remind of each other apparently by the presence of a chemical group like a sulfurous one or an aromatic fluoro... but I think that may have something to do with particular harmless pharmacological or metabolic effects involving those groups. (For example I feel like my body can taste the sulfurous groups in Z-drugs, modafinil, 2C-T-x).

Don't underestimate how you (and many others) may have developed a bias that reinforced itself, which makes it more like a belief or prejudice that is partially self-fulfilling.

Some of those comparisons don't seem really fair like U-47700 vs opiates which I doubt has much to do with the halogens, although dichlorophenyls like there can be powerful groups, perhaps interacting rather strongly with receptors or enzymes. Not because of halogens an sich but because of the electronic properties I think. 4-fluoroamphetamine doesn't seem unnatural feeling to me, just rather serotonergic / less one-sided with the monoamine activity. 2C-C is an example of a very benign substance, it seems.
So the effect of a halogen group highly depends on the chemical and should not be generalized into such a bias. (I probably do have something of a bias myself, but am aware of it - I am for example partial to fluoro compounds but don't think the presence of such a group can actually predict anything about a substance)

Ketamine feels less unnatural than deschloroketamine to me by the way...

 

[WSH]

Your post is based on a fundamental misunderstanding of chemistry and pharmacology. There is nothing "unnatural" or inherently bad about drugs containing halogen atoms. Our bodies contain many halogens atoms (sodium chloride, triiodothyronine, etc).

Hydrochloride in the stomach is also a good example, it contains the halogen Chloride!

 

[Morninggloryseed]

Hmmmm, all the chlorinated and brominated drugs ive had feel great. Haloheaven.

 

[serotonin2A]

I do find it curious how unrelated drugs can feel like they remind of each other apparently by the presence of a chemical group like a sulfurous one or an aromatic fluoro... but I think that may have something to do with particular harmless pharmacological or metabolic effects involving those groups. (For example I feel like my body can taste the sulfurous groups in Z-drugs, modafinil, 2C-T-x).

That is an interesting point: some drugs have a particular or bad taste that can be perceived when the drug is secreted in saliva. However, I didn't really think that was what the OP was referring to -- I thought the post was about the subjective interoceptive drug response, which is generally a pharmacological effect. The latter type of response is not usually a direct consequence of the specific chemical groups present in a molecule.

 

[aced126]

I do find it curious how unrelated drugs can feel like they remind of each other apparently by the presence of a chemical group like a sulfurous one or an aromatic fluoro... but I think that may have something to do with particular harmless pharmacological or metabolic effects involving those groups. (For example I feel like my body can taste the sulfurous groups in Z-drugs, modafinil, 2C-T-x).

I have a feeling this might have something to do with similar metabolism of these particular functional groups. It could also be due to placebo - if you weren't aware of the structures of these sulphurous drugs, would you feel the same way?

 

[Solipsis]

Nobody could refute the possibility of placebo but I am skeptical because I am not aware of any particular bias for or against sulfurous groups, nor did I make any link before my observations and sensations... and there are plenty of other groups or atoms in many drugs that go by pretty much unnoticed by me. (Where's the phosphors at? ) Also I believe that 2C-T-X for example are *extensively* metabolized and I can imagine various ways of things like sulfinyls or sulfide organic compounds to generally metabolize or react and there are also good reasons why we are sensitive to tasting and smelling such sulfurous compounds and are generally aversive to them [putrefying reactions etc].

But something like aromatic fluoros is much more vague than that and open to interpretation and suggestion. I guess that could be more like a placebo or bias meme. Or at the very least an association I made for drugs I appreciate that could be purely coincidental and any remote similarity could be imagined.

I know the OP didn't directly refer to any of this but still there are myths about SAR implied that are addressed this way. The reality about this is nuanced: generally functional groups being natural or not, or implying toxicity simply by being a part of any structure is an incorrect distinction. But not always: some groups may tend to metabolize in similar ways, nitriles may not be the same as ionic cyanide but are often still not good for you since it can often still get released, ionic chloride has very little to do with any halogens on a structure, etc.

As for the benzos: I doubt for days that just the presence of halogens has anything to do with carcinogenicity of benzos, why, because chlorine gas is so horrible? But to be fair, SAR is endless rules to which there are endless exceptions and more rules, to infinity. There could have been haloacetic acid as metabolite if the halogens were some sort of aliphatic, there could be some kind of problem but just none of this witchhunt seems to be based on real suspicions or evidence. But that doesn't mean it's always all bullshit. is my point.

 

[DotChem]

^..^^ Sulfur containing drugs interact in a non-specific manner that are qualitatively different from ordinary interactions between drug and receptor ie electrostatic, hydrophophibic, H-bonds... etc. These were nicknamed thiophilic interactions and are unique with sulfur containing drugs especially sp3 sulfur like in MTA. They have been taken advantage of to purify certain proteins that have particular affinity for sulfur containing compounds. For example immoglobulins ar notorious for binding sulfur compounds.

Non-specific protein binding affect the drug distribution and could have a dramatic effect like with psychotropics where a slight difference in drug concentration/distribution can result in huge difference in subjective biological effect (eg a drug binds to the PFC and other brain areas like the VTA or selectively accumulated in the hyppocampus..etc. The effect (kinetic AND thermodynamic control) will be dependent on the dose as it is distributed (un)evenly depending on non-specific affinity for this or that area!). I don't know how to put it but I hope you get the point!

Similarly with fluoro (but I am not sure if it is the case with other halogens), certain brain areas are fluorophilic (a term coined by.. DotChem ie they'll accumulate pretty much ANY compound bearing a Fluorine atom regardless of its structure, whether it is in the form of simple fuoride ion or fluoro-substituted molecules: a very stricking case is the pineal gland. Almost ALL PET imaging scan of 19-Fluorine labeled drugs showed a large concentration of the label in the pineal gland!! why, how fluoro containing compounds like to accumulate in the pineal?? go figure! That is why people are blaming fluorine in water as neurotoxines with good reason as it leads to calcification of the gland.

So some brain areas may have more affinity for thio containing compounds or fluoro containing molecules regardless of structure as long as it contains a F or S. I am not sure if such thing happens with a Chloro. Bromine or Iodo..(Oh wait! didn't the thyroid gland accumulate Iodo compounds or is it only Iodide ion???
So it may have to do with pharmacokinetic rather that pharmacodynamic...but who knows??

 

[serotonin2A]

Similarly with fluoro (but I am not sure if it is the case with other halogens), certain brain areas are fluorophilic (a term coined by.. DotChem ie they'll accumulate pretty much ANY compound bearing a Fluorine atom regardless of its structure, whether it is in the form of simple fuoride ion or fluoro-substituted molecules: a very stricking case is the pineal gland. Almost ALL PET imaging scan of 19-Fluorine labeled drugs showed a large concentration of the label in the pineal gland!! why, how fluoro containing compounds like to accumulate in the pineal?? go figure! That is why people are blaming fluorine in water as neurotoxines with good reason as it leads to calcification of the gland.

Could you post the studies illustrating this phenomenon across multiple fluorine-18 PET tracers? Note that it is F-18, not F-19. My understanding is that [18F]DOPA accumulates in the pineal gland but that is thought to be specific accumulation. I looked over reports from a variety of other F-18 labeled PET tracers and none of them accumulated in the pineal gland or accumulated non-specifically in particular structures. Such an effect should be obvious when comparing the distribution of F-18 and C-11 labeled tracers.

"PET imaging studies in nonhuman primates with 11C-fallypride showed radiotracer localization in dopaminergic brain regions such as caudate, putamen, thalamus and cortex. This regional localization of 11C-fallypride is similar to that observed previously for 18F-fallypride."
http://www.sciencedirect.com/science/article/pii/S0968089603007077
http://www.sciencedirect.com/science/article/pii/S0969805199000128

"The D-2 antagonist, haloperidol effectively blocked binding of [18F]fallypride to the striata, whereas the D-1 antagonist, SCH 23390 did not block the specific binding."
https://www.ncbi.nlm.nih.gov/pubmed/7627142

"In our study of 18F-MEM pharmacokinetics in mice and in one monkey, relatively high uptake and retention levels of the radiotracer in the brain were observed. Approximately 75% of the total uptake in mouse brain was found in the hippocampus and in the cerebral cortices, regions known to contain the highest densities of the NMDA receptors. The specificity of the 18F-MEM binding in mice brain was attested by the reduction of the activity concentration after co-injection of 18F-MEM with (+)-MK-801. Binding of 18F-MEM to the PCP site of the NMDA receptor channel was also confirmed by the reduction of radioactivity concentrations in the cortical areas, striatum, and in the cerebellum after pretreatment of the monkey with therapeutic doses of memantine and a pharmacological dose of (+)-MK-801."
https://www.ncbi.nlm.nih.gov/pubmed/9639292

"To our knowledge, (-)-5'-18F-delta-8-THC is the first cannabinoid positron-emitting derivative synthesized to date. This molecule was designed for visualizing cannabinoid binding sites in the primate brain using positron emission tomography imaging and was also used to study cannabinoid biodistribution in mice. The results from the PET experiments discussed here show a number of similarities with those obtained by autoradiographical visualization of cannabinoid receptors in the brain using [3H]CP-55,940."
http://www.sciencedirect.com/science/article/pii/0091305791903545

"(-)-[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. ...Autoradiography of rat brain 3 h following i.v. injection of (-)-[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. ...These studies show FEOBV maps cholinergic areas with high specificity in vivo..."
https://www.ncbi.nlm.nih.gov/pubmed/9776130

"PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by [¹⁸F]flumazenil as for [¹¹C]flumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil."
http://www.sciencedirect.com/science/article/pii/S0969805104001672

Note that none of these F-18 labeled tracers showed significant non-specific accumulation in the pineal glad or in other brain areas.