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Author Topic: Benzos have an interesting SAR-let’s explore it  (Read 7266 times)

Offline Jega (OP)

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Benzos have an interesting SAR-let’s explore it
« on: September 15, 2015, 04:08:16 AM »
Back on opiophile there was a very old thread written by Resorcinol titled Benzos have an interesting SAR-let’s explore it. It was a great primer on the chemistry of different benzodiazepines and how different changes in their chemical makeup change their effects. I hope one day it can come back since it’s better than what I put together but in the spirit of that thread I put this together in the hope that it can help someone.

What is a benzo? A Benzodiazepine is any drug that fits the profile of a benzene ring fused to a diazepine ring. I want to note at the beginning that most of the classical benzodiazepines contain a phenyl ring (although it doesn’t have too). As you can see pictured below. 

* Benzodiazepine3.jpg (11.36 kB . 248x178 - viewed 288 times)

Different benzodiazepine drugs have different negatively charged atoms attached to this central structure. The numbering system you see pictured above is used to refer to where electively negative atoms are commonly bonded. For example, diazepam is 7-chloro-1-methyl substituted.

* diazepam.jpg (6.99 kB . 232x269 - viewed 347 times)

The two most common sites for substitution to the central structure are at the 7 position of the benzene ring and the 2 position of the phenyl ring. A substitution on the 2 position of the phenyl ring greatly increases potency, and it also greatly pushes the effect profile towards being a hypnotic. It’s common to find drugs without the substitution at the 2’ position and still have an electronegative at the 7’ position, Diazepam comes to mind, but those that do carry an electronegative at the 2’ position are usually already substituted at the 7’ position since it’s one of the first places one can go to increase potency.

Consider these two, Alprazolam (Xanax) and Triazolam (Halcion). Alprazolam is considered one of the most potent anxiolytics while Triazolam is considered such a potent hypnotic it’s banned in many European countries. The only difference between these two is the 2-chlorophenyl change. Note that both of these contain Triazole rings, while the vast majority of Benzodiazepines do not.  The addition of a triazole ring vastly increases potency and usually decreases time of onset of effects.

* Alprazolam Triazolam.jpg (15.02 kB . 342x195 - viewed 333 times)

Not every benzodiazepine needs to be a 1,4-benzodiazepine meaning that its diazepine ring has nitrogen atoms at the 1 and 4 positions. Consider Clobazam which is a 1,5-benzodiazepine. 1,5-benzodiazepines generally are weaker compared to traditional 1,4-benzodiazepines, but can still be effective at higher dosages.

* Clobazam-2D-skeletal.jpg (9.2 kB . 199x220 - viewed 282 times)

Is Etizolam still a benzo without the benzene ring? Well it depends on how you look at it. To quote wiki since I can’t say it better. “The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine.” But we’ve already expanded our original definition of what a benzo is beyond the traditional 1,4-benzodiazepine. In my book it acts on the correct receptors, caries the same effect profile, and follows the same rules on its central structure as traditional Benzos. It’s a benzo in my eyes.

* etizolam.jpg (14.18 kB . 336x298 - viewed 315 times)

Etizolam and other thienodiazepines also show no characters of being weaker compared to traditional Benzos by the addition of the thiophene ring. I wanted to note this as we are likely to see more thienodiazepines coming down the RC pipeline.
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Offline Zoops

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #1 on: September 15, 2015, 04:32:19 AM »
What if you take away the ethyl group on the thiophene ring in etizolam and substitute a halogen (at the 2- or 3- position)? This is the main difference between etizolam and other traditional benzos - no halogen or nitro-substitution at the place in the molecule corresponding to the benzo-fused ring in a benzodiazepine.
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Offline Jega (OP)

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #2 on: September 15, 2015, 04:34:13 AM »
What if you take away the ethyl group on the thiophene ring in etizolam and substitute a halogen (at the 2- or 3- position)? This is the main difference between etizolam and other traditional benzos - no halogen or nitro-substitution at the place in the molecule corresponding to the benzo-fused ring in a benzodiazepine.
I would be very curious to see a potency equivalent without the halogen. But since it bonds nicely I can see future thienodiazepines using a halogen as well.

If you took away the Halogen and the Triazole ring and the 2-chlorophenyl, I wonder how close to a 1 to 1 with Diazepam we would get.
« Last Edit: September 15, 2015, 04:36:32 AM by Jega »
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Offline Zoops

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #3 on: September 15, 2015, 04:38:31 AM »
I think if you had a halogen on the thiophene ring, it would have to be at the 3-position, as it would be a bit unstable to simple hydrolysis if it was bonded at the 2-position of thiophene.
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Offline Jega (OP)

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #4 on: September 15, 2015, 04:50:47 AM »
I think if you had a halogen on the thiophene ring, it would have to be at the 3-position, as it would be a bit unstable to simple hydrolysis if it was bonded at the 2-position of thiophene.
Well every thienodiazepine I know of holds onto the Sulfer where it is even Brotizolam which has a Bromine at the 2 spot instead of the methyl group.
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Re: Benzos have an interesting SAR-let’s explore it
« Reply #5 on: September 15, 2015, 05:30:34 AM »
My bad.
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Re: Benzos have an interesting SAR-let’s explore it
« Reply #6 on: September 15, 2015, 09:21:09 AM »
Hey Jega
I got idea
Let's not talk
About benzos
Cuz I'm feening
Like a mofo

J/k

Carry on

I'll just stay outta
This thread
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Re: Benzos have an interesting SAR-let’s explore it
« Reply #7 on: September 15, 2015, 09:33:49 AM »
my thienobenzo, Olanzapine is a proven agent to fight off neurotoxicity by methamphetamine.

but it's a little known fact but that's why I use them.
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I do not condone or support any illegal activities. All information is for theoretical discussion and wonder.
All activities discussed are considered fictional and hypothetical. Information of all discussion has been derived from online research and in the spirit of personal Freedom.

Offline Jega (OP)

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #8 on: September 16, 2015, 12:36:47 AM »
my thienobenzo, Olanzapine is a proven agent to fight off neurotoxicity by methamphetamine.

but it's a little known fact but that's why I use them.
Why am I not surprised. The truth is when it comes to the chemistry and effect profile, we are just scratching the surface with thienobenzos.

* 261px-Olanzapine_Structural_Formulea.jpg (11.1 kB . 261x240 - viewed 260 times)
also a great demonstrator that not everything needs a traditional phenyl ring.
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Re: Benzos have an interesting SAR-let’s explore it
« Reply #9 on: September 16, 2015, 02:01:50 AM »
Truth be told olanzapine is in a completely different class of pharmaceutical agent than etizolam, which is a thienodiazepine, whilst Olanzepine is a benzothienodiazepine. Why is this not lost on anyone? Olanzepine has a completely different pharmacological profile than eitzolam as well. It does not appreciably activate GABA receptors, instead, a whole slew of D2, M, NE, and H1, and others as antagonists, rather than eitzolam at the GABA receptor as a pure agonist.

When they were trying to patent olanzapine over etizolam (this issue was undoubtedly raised by a first year know-nothing patent examiner) you'd have a very easy time of it because they're based on completely different polyheterocyclic nuclei.

Completely worlds away from etizolam's effects.

But I don't doubt for a second that it mitigates the negative effects of methamphetamine use.
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Offline Jega (OP)

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Re: Benzos have an interesting SAR-let’s explore it
« Reply #10 on: September 16, 2015, 02:14:14 AM »
Truth be told olanzapine is in a completely different class of pharmaceutical agent than etizolam, which is a thienodiazepine, whilst Olanzepine is a benzothienodiazepine. Why is this not lost on anyone? Olanzepine has a completely different pharmacological profile than eitzolam as well. It does not appreciably activate GABA receptors, instead, a whole slew of D2, M, NE, and H1, and others as antagonists, rather than eitzolam at the GABA receptor as a pure agonist.

When they were trying to patent olanzapine over etizolam (this issue was undoubtedly raised by a first year know-nothing patent examiner) you'd have a very easy time of it because they're based on completely different polyheterocyclic nuclei.

Completely worlds away from etizolam's effects.

But I don't doubt for a second that it mitigates the negative effects of methamphetamine use.
olanzapine: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine

I had to look it up but there it is. And that is wierd. It sure doesn't read like etizolam which is:
7-(2-Chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene

Also very odd that olanzapine is a 1,5 benzodiazepine.

I can see it having it's own patent.
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Re: Benzos have an interesting SAR-let’s explore it
« Reply #11 on: October 15, 2015, 07:43:14 AM »
This was Resorcinol  original post:

Benzos have interesting SAR, lets explore it
SAR = structure activity relationships.

Opioid mu agonists have fascinating SAR too, but there are SO many classes of opioids that covering SAR for them coprehensively would be a mile long post by anybody's standards. The morphine rule is a succinct way to look at opioid SAR, but there are times when it can be violated too.

Benzos on the other hand really only come from one chemical "class": a diazepine ring fuzed to a benzene ring (hence benzo-diazepine), and a third aromatic ring attached at position 5 (usually a phenyl, but sometimes not).

Lets look at the "core" of the typical benzodiazepine structure:


The numbering goes like this: It starts at the N to the left of the CO (carbonyl) group (which makes it an amide): that N is position 1. Then we move clockwise. Carbon 2 has the double bond to oxygen (carbonyl group). Carbon 3 is the next moving clockwise. Position 4 is the other nitrogen on this diazepine ring (this is a 1,4 diazepine ring, in some benzos the N positions are different). Position 5 is the carbon after that, where the phenyl ring attaches. Continuing clockwise, we SKIP the next carbon where the rings fuse because it already has four covalent bonds integral to the structure: one is not a hydrogen that we can swap out for a different substituent. Carbon 7 is next (this is where diazepam has a Cl if this is confusing... actually there has to be an electronegative sub here for any significant activity but we'll get to that). Carbon 8 and Carbon 9 are next continuing clockwise. The carbon to the clockwise of 9 is, again, unavailable for substitutions, so it gets no number.

Moving to the phenyl ring attached at 5: we'll start where it attaches and go clockwise (although keep in mind since this is a single bond and the phenyl can spin all the way around, it doesn't matter whether I go clockwise or counter clockwise in numbering, and some diagrams may show the 2' substituent on the left instead of the right). Where it attaches is 1' (the ' means "prime" --- we've already used the "primary" set of numbers, and side CHAINS get greek letters, detached RINGS get numbers from a new "set" by using the prime ' symbol). The next carbon is 2', then 3', 4', 5', and finally 6'.

That's the numbering.

Now we can talk about the SAR of benzos. SAR of benzos is fascinating, and at the same time not incredibly difficult to talk about since all benzos come from the same chemical class pretty much, unlike opioids (the exception are the z-drugs, which are "benzos" from new classes, so one day this may no longer be so simple to discuss).

Lets talk about position 7, a carbon on the main two fused ring part, on the benzene side. Position 7 needs an electronegative substituent. Without this, activity is greatly diminished. I doubt you'll find a benzo without an electronegative sub here. On diazepam, and many others, this sub is a Cl (chlorine) atom.

Electronegativity is, in a nutshell, how strongly a particular element attracts electrons towards its quantum orbitals. It's easy to think about electrons "orbiting" the positively charged nucleus like planets orbit their sun, but that isn't really correct; it is OK however to view it that way, as it still "works" at this basic level of chemistry: just talking about electronegativity. If you're interested in really understanding electron orbital behavior, look up the "azimuthal quantum number" (one of the many quantum numbers applied to particles). So basically: how strongly does this element's atom attract electrons towards it? That's electronegativity. More electronegative --> greater attractive pull on electrons. Less electronegative --> weaker pull. Atoms that need to fill their valence energy level (which is one of the "principal quantum number" levels) by gaining electrons (their outer energy level is closer to having 8 electrons than 0) are more electronegative. Atoms that are smaller in radius are more electronegative because their outermost electrons are closer to the positively charged nucleus, and the electromagnetic force becomes exponentially stronger as distance between the charged objects/particles decreases.

So if one looks at the periodic table: electronegativity increases as one moves from the lower left of the table to the upper right (we'll ignore the noble gases for this). So cesium is the least electronegative (it's electropostive actually, if compared relativistically to the right of the table), and fluorine is the most electronegative. All of the Halogens are pretty highly electronegative. Nitrogen, sulfur, and oxygen are also pretty highly electronegative. Some polyatomic subs that are electron attracting include: nitro, and pseudohalogens (like -CF3) . There are more but they're important for benzos.

So position 7, we need an electronegative group. Diazepam, oxazepam (have chlorine there) ; nitrazepam, flunitrazepam, clonazepam (have nitro there) ; bromazepam, phenazepam (have bromine there).

Position 2 should keep the carbonyl group UNLESS it is part of a triazolo ring!

Position 1, the nitrogen that is part of the amide. Important. This one divides benzo users more than any other variable. Having this amide be tertiary (having the hydrogen replaced with a substituent, a methyl group almost always, but there are exceptions like flutoprazepam) increases potency slightly. More importantly, it shifts the selectivity profile of the benzo such that it becomes much more hypnotic than anxiolytic. Hardcore hypnotic lovers will say "not tertiary amide, it's garbage". On the other hand, those that prefer the more anxiolytic benzos say that having the amide tertiary causes too much disinhibition, memory loss, and sedation; they'll say that the small potency boost isn't worth those other effects of this change. This comes down to preference: while all benzos are nonselective mostly, they are a bit selective, and having that amide tertiary instead of secondary boosts affinity to a1 subunits of GABA(A)bzd, which is the "hypnotic" site.

Position 2' is the major spot utilized to increase potency. Having an electronegative group on 2' GREATLY boosts potency. Clonazepam is 2'-chloro-nitrazepam, and it's 10 to 20x more potent! Usually a halogen is utilized here to replace the hydrogen. All of the halogens are electronegative enough. Fluorine is the most electronegative atom, and increases potency the most when subbed at 2' (BUT this also creates benzos that qualitatively cause worse memory loss; flunitrazepam is an example). One interesting varient is when the phenyl ring is scratched altogether for a pyridine ring. It's a six membered aromatic too, but has a nitrogen at 2' spot instead of a carbon. Nitrogen is already electronegative, so a substituent is not needed (it couldn't be added to the N in pyridine anyway, it's already got three bonds). The N in the pyridine ring acts as the electronegative atom in the 2' spot. This is the case in bromazepam. A whole new class of benzos with a pyridine ala bromazepam could be ushered in, and if the euphoria of bromazepam speaks for the class, then they might be blockbusters.

The ring at 5 should NOT be a saturated ring. This GREATLY reduces potency. It has to be aromatic (like phenyl or pyridine).

One final thing: we can ignore the rule about tertiary amide at 1 and carbonyl always being at 2 in the case of triazolobenzodiazepines. Those positions become part of the triazolo ring, and the rules about hypnotic or anxiolytic selectivity are something I'm not sure of in this instance. One thing I do know is that the triazolo-counterpart of any regular non-triazolo benzo is more potent. Alprazolam and triazolam are the two most well known of this type.

The reason that some spots should have electronegative atoms has to do with parts of the GABA(A)bzd receptor active site having partial positive charge. The concentration of partial negative charge around the electronegative groups is attracted to protein residues in the receptor with partial positive regions: this improves overall affinity by dipole-dipole interaction.

The non-electronegativity related substituents have to do with steric effects more than electronic effects, although hydrophobic interactions probably play a part in seating nonpolar parts of the molecules in the receptor.

Most of chemistry though (since it's the study of how the elements' ELECTRONS interact to form more stable quantum orbital states through bonding), and indeed most of our everyday life Newtonian forces do boil down to the electromagnetic interaction, which is mediated by our friend the photon.

There are other exotic benzos with strange substituents, but this covers the basics. Have fun getting loopy and forgetting stuff! If I made any goofs let me know.
It's cool. I posted it mainly for people to refer to if they want to gauge how potent a benzo that there's scarce info about online. Like, say, tetrazepam. With a little digging you find that it's a very weak benzo, about 50 mg tetrazepam = 7.5 mg diazepam.

However if you couldn't find that info and needed to estimate potency, you can glance at the SAR rules.

Note that tetrazepam is the same as diazepam except for one thing: the detached aromatic ring at position 5 has been partially saturated. One of the rules says that saturating that ring GREATLY reduces potency. So while you wouldn't know the equivalence that I gave above EXACTLY based on that, you would know that it's potency would be SIGNIFICANTLY less than diazepam, and could dose conservatively based on that knowledge and eventually settle on your own potency estimate.

Tetrazepam is a good example benzo to demonstrate the rule about the substituent at 5. It's a non aromatic ring (a cyclohex-1,2-ene), and as the SAR rule about that ring states, that should drastically reduce the potency (and it does, tetrazepam is very weak. It's even weaker than chlordiazepoxide.)
This seems to show that having a six membered AROMATIC ring at 5 is even more important than having the carbonyl at 2. Tetrazepam has the carbonyl at 2, chlordiazepoxide doesn't [it has a methylamine substitution at 2]. Yet chlordiazepoxide is STILL stronger than tetrazepam! Chlordiazepoxide is partially metabolized into nordiazepam and oxazepam, which probably accounts for most of its activity, although the parent drug isn't totally inactive. Chlordiazepoxide could nonetheless be considered a prodrug due to oxazepam and nordiazepam having a much stronger agonism on the bzd receptors. So perhaps the 2 carbonyl and the aromatic ring at 5 are equally important, and chlordiazepoxide is only stronger than tetrazepam because it has active metabolites [nordiazepam and oxazepam] from the process of chlordiazepoxide being deaminated at 2 and then oxidized to yield a carbonyl group; and the oxide moiety at 4 is reduced liberating the oxygen and leaving an uncharged nitrogen.

Unlike tetrazepam, there are benzos out there that one could conceivably acquire from IOPs or RC companies that probably have NO potency data floating around out on the internet.

Sulazepam is one that I can't find potency data on, BUT, lets look at its structure: It is IDENTICAL to diazepam except for one feature -- the carbonyl is changed to a carbon double bonded to a sulfur (instead of the carbonyl's carbon double bonded to an oxygen). The C-double bond-S moiety is normally a lot more unstable than the C-double bond-O moiety, but it is stabilized in the thioamide situation (where a N is directly adjacent to the C-double bond-S ; so it's the sulfur analog of a regular amide). The adjacent N stabilizes the thioamide by virtue of having a free electron pair: this pair is pulled towards the C-double bond-S structure, analogous to what happens with the carbonyl in a regular amide. This creates a resonant "partial" double bond between the nitrogen and the adjacent carbon with the double bond to the oxygen or sulfur. Thus, the electronegative oxygen or sulfur can hog the electrons they are sharing with the carbon more, because carbon is getting a little bit of time to play with the lone pair from the nitrogen. This extra time the oxygen or sulfur gets with the electrons from the carbon doesn't just give it a more prominent negative partial charge (although this does happen it's not the importance of the situation), it also acts to make the double bond between the carbon and sulfur or oxygen MORE STABLE. With carbonyl (C double bond to O), this stabilization by being part of an amide isn't needed; the carbonyl can exist alone, although due to not being stabilized, it will exhibit enol-keto tautomerism in these cases (look at hydrocodone / oxycodone and how they can form "enol acetates" -- the enol acetate of hydrocodone is "thebacon"). The C-double bond-S, however, would be VERY unstable without having an adjacent nitrogen --- so you're unlikely to find many cases of C-double bond-S (there are exceptions) outside of the thioamides. Since the thioamide requires greater stabilization from nitrogen lone pair delocalization to keep the sulfur double bonded to the carbon atom, the bond from N to C will be "double bond like" more often than in a regular amide. This is all relevant because it may change potency a little bit in the benzo. HOWEVER... back to sulazepam....

The only difference between it and diazepam is that that one oxygen double bonded to the C at position 2 is replaced with a sulfur. Sulfur is in the same periodic table group (chalcogens) as oxygen, so the valence electron situation is the same; the double bond to sulfur is an analog to the double bond to oxygen. The only difference is that stated above: more delocalization of the N free electron pair is needed to stabilize the carbon to sulfur double bond in thioamides than the carbon to oxygen double bond in amides (this is likely simply because sulfur has a larger atomic radius and its valence principle quantum number energy level is further from the nucleus and its positive charged protons more often than in the smaller atomic radius oxygen atom. It's because of this that sulfur has diminished capacity to hog shared electrons from carbon in the double bond formed with carbon. However, the nitrogen can compensate by delocalizing its free electron pair to carbon more often, which weakens carbon's hold on the electrons it's sharing in the double bond to sulfur, so sulfur can attract them more often --- often enough to stabilize the bond! So thioamides are stable). This does mean, though, that thioamides are even WEAKER bases than amides (amides are already pretty weak bases), since nitrogen is having its lone pair delocalized towards the carbon more often than in amides. In AMINES (no carbon double bonded to a chalcogen is adjacent to the nitrogen atom, any adjacent carbons are less needy), basicity is much stronger as nitrogen keeps its lone pair for the most part which can then accept a coordinate covalent bond to a proton (unless it's IN or BONDED TO an aromatic ring, in which case it sometimes sees its lone electron pair delocalized into the aromatic pi bond; greatly so if the amine is IN the aromatic ring [eg pyridine] and somewhat so if it's BONDED TO the aromatic ring [eg 1-amino-benzene]; in these cases basicity is reduced also).

So since for the most part sulazepam is analogous to diazepam, and they differ principally in the degree that the thioamide/amide nitrogen has to delocalize its free electron pair to form a partial double bond to the adjacent needy carbon, we can surmise that sulazepam is probably similar in potency to diazepam.

I don't know the actual potency of sulazepam. If its exactly the same potency as diazepam, though, this would tell us something: 1)that the degree to which the free electron pair stays with the nitrogen in the amide/thioamide doesn't effect potency and that the decreased conc of negative charge around the nitrogen doesn't effect potency in the thioamide AND 2)that the larger atomic radius of sulfur vs oxygen doesn't effect potency.
If, however, it was slightly stronger or weaker than diazepam, or it was slightly more hypnotic or anxiolytic selective, it would mean the exact opposite: that one of the above things does in fact effect potency/selectivity and is SAR-relevant.
However, with high confidence, we can assume that sulazepam is AROUND the same potency as diazepam, and probably feels quite subjectively similar, since aside from the differences mentioned, from a valence POV it's a very close relative of diazepam -- it's an analog not far separated from diazepam at all.


it
Here's the structures of some RARE and EXOTIC benzos. The first will be the sulazepam talked about above.
Keep in mind that one could, in theory, special order a benzo that isn't even LISTED anywhere online as a benzo. There have been thousands of benzos tested, but I'm sure many many were never even given a name, and thus won't appear on wikipedia's long list of benzos, or probably anywhere online either. They also wouldn't be explicitly scheduled. While they'd certainly fall under the analog act, customs officials most likely do not understand IUPAC nomenclature, and would have NOT A CLUE what it was and would assume some obscure organic chemical that a researcher ordered or something. That's if they even opened the package. If it came from a US lab, it wouldn't even go through customs. The lab just might synth these things for you too, quite possibly not realizing the psychoactivity of what you're requesting. Organic chemists aren't all pharmacologists too ---- many probably wouldn't recognize a request for a likely tranquilizer when IUPAC nomenclature is used (you'd have to make DAMN SURE you got the IUPAC name right, though!). I've always wondered if anyone's done this and tried a super obscure benzodiazepine. I wouldn't do it because I'd be afraid of somehow being arrested under the analog act, the lab messing up and making a different chemical than the one I asked for (could be toxic), taking benzos that have not been evaluated for toxicity in ANY country .... who knows, some obscure benzos could be psychoactive but carcinognic too. Just too much risk. But fun to think about. Anyway, some obscure, but NAMED and KNOWN benzodiazepines:
sulazepam

tetrazepam

That's the one with the partially saturated ring I talked about in the post above. Very weak 50 mg = 7.5 mg diazepam
meclonazepam (3-methylclonazepam)
http://upload.wikimedia.org/wikipedi...clonazepam.png
lopirazepam

fludiazepam (2'-fluoro-diazepam)
http://upload.wikimedia.org/wikipedi...azepam.svg.png
flutoprazepam

adinazolam
http://upload.wikimedia.org/wikipedi...azolam.svg.png
bromazepam

All of these demonstrate something unusual from the "norm" in benzos. Sulazepam changes the carbonyl at 2 which is a feature of the vast majority of other benzos. Tetrazepam has a partially saturated detached ring at 5 (decreases potency).
Fludiazepam is probably a pretty strong hypnotic. It's not particularly unusual but it's rare for sure.
Meclonazepam has a methyl substituted at 3, which is very unusual, and apparently gives it antiparasitic activity in addition to bzd agonist activity.
Lopirazepam has the fuzed ring system altered. The benzene ring fuzed to the diazepine is changed to a pyridine.
Flutoprazepam shows us a case where a substituent at 1-N other than methyl to make the amide tertiary works very well; this benzo is popularly abused in Japan.
Adinazolam has an unusual substituent on the triazolo. This apparently is very similar to alprazolam, but has even more pronounced "antidepressant" effects than alprazolam's supposed antidepressant effects.
Bromazepam is a common benzo in a lot of countries with an unusual feature. The detached ring at 5 is a pyridine instead of a phenyl. It attaches offset one position from the N, placing the N at 2', such that it can act as the electronegative atom in the 2' spot.
Position 2' is the major spot utilized to increase potency. Having an electronegative group on 2' GREATLY boosts potency. Clonazepam is 2'-chloro-nitrazepam, and it's 10 to 20x more potent! Usually a halogen is utilized here to replace the hydrogen. All of the halogens are electronegative enough. Fluorine is the most electronegative atom, and increases potency the most when subbed at 2' (BUT this also creates benzos that qualitatively cause worse memory loss; flunitrazepam is an example).
I think you're misreading what this says. I don't believe the increased memory impairment is due to the more electronegative 2' substitutent. I think it's largely due to the the nitro grouping on the 7 carbon. Are you aware of a strongly amnesic benzo that doesn't have the nitro group there and isn't a triazolo or other expansions on the simple 1,4-benzodiazepine? I don't have all the benzos memorized or even very many of them, to be honest.
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