View Full Version : not-PHENethylamines!
So...I was considering our friend methamphetamine, and the structurally similar stimulants cyclopentamine and propylexedrine and became curious what we could do to these all too forgiving PEA or amphetamine backbones.
Most interesting to me is the substitution of the phenyl ring itself with..oh I don't know... thiophene? furan? Can anyone elucidate me on the topic of how these rings affect the receptor binding properties?
I suppose someone must know about this since we've already tried weird shit like benzodifuranyl 'stead of phenyl...
PS: I'm n1k, a chemistry fan who's not posted here in some time. I like what LT grew into- legitimate chemistry exploration from the ashes of a million meth topics.
You can't just simply add some chemicals to swap those groups out. And if it was practical, I can guarantee you that those chems would be scheduled.
You can't just simply add some chemicals to swap those groups out. And if it was practical, I can guarantee you that those chems would be scheduled.
I meant a structural substitution, not a one step synthesis from one to the other.
Oh! Synthesis of ethylaminopyridines by the reaction of isomeric benzaldehyde pyridylhydrazones with sodium ethoxide ...
4-aminopyridine itself seems to have some interesting properties, it prolongs action potentials apparently.
stateofhack
2008-06-17, 08:54
OK..............iNb4SoFh
fuck :mad:
incorporated
2008-06-18, 00:13
OK..............iNb4SoFh
You're a legit poster usually but why do you post this in every thread?
Most interesting to me is the substitution of the phenyl ring itself with..oh I don't know... thiophene? furan? Can anyone elucidate me on the topic of how these rings affect the receptor binding properties?
I'm guessing it would fuck it all to hell.
Generally speaking, the characterization of receptor protiens tends to break them into specific subunits, or "sites," which serve a specific purpouse. To a great degree, this is why SARs can be so damned forgiving - as long as one spacially has things like "negative charge somewhere over there," or "positive charge over here," then it really doesn't matter much what skeleton holds those charges in those relative spacial locations, or WTF is actually holding the charge.
Regions which actually look for benzene tend to look for two things. Namely...
- that it is aromatic (which is why benzedrex is about an order of magnitude less potent than its identical aromatic methamphetamine), and...
- that it is completely nonpolar and carries no intrinsic charge.
Generally speaking, the four things a receptor can check for are positive charge, negative charge, aromaticity, and chargeless lipophilic hydrocarbon; the receptor for THC, for instance, is very sensitive to that last one.
'n different receptors have different spacial preferences for each of these components. The adrenoreceptor involved in decongestion, for instance, prefers its negative charge to be at the 3 and 5 positions on the ring for optimal selectivity, and likes a large hydrophobic substituent on the amine, while the presynaptic noradrenergic receptors appear to prefer negative charge at the 2 and 6 position, and a lump of ammonia much more signifigant than average.
Everything else is just metabolic fucktardery.[/b] It can be pretty cool fucktardery, all in all, but... the methyl group on amphetamine is nothing more than a nonpsychoactive MAO inhibitor. The methyl group on the 4-position of DOM is pretty damned close to doing nothing but preventing 4-hydroxylation. A fluorine in place of a hydroxyl group at the 3-position will be unaffectable by catechol ortho-methyltransferase. 'n so on.
From an SAR position, this makes it pretty easy to cook up some elaborate ring systems; the benzodifuran, for instance, is essentially identical to the 2,5dioxysuperpsychedelics already - the charge is on the right place, and masked to allow passage through the BBB. Similarly, 3,4-methylenedioxy-6-chloro-7-methoxy-2-methyl-2,3-dihydroindole is essentially identical to b-methoxy-DOC, despite being a giant fucktarded tricyclic ring system. 'n the benzodioxole analog of methamphetamine, commonly known as MDMA is just an enzyme-inhibited, minimally-masked n-methyldopamine.
One can create just about any bitchin' ring system one wants. In fact, if you're looking for "the tweak that never ends," it's pretty easy to cook up some obscenely metabolically-resistant species, while if you're looking for a new flavor of trip, polycyclic designer psychedelics can be pulled out one's arse for a lifetime.
...but if you deviate from benzene where the benzene should be, you're fucked. If you use any aromatic not of 6 carbon, the potency drops a little bit. If you lose aromaticity, the potency drops a fuckload.
'n if you start adding charge [i]in the ring rather than on the ring, it... doesn't even resemble what it is looking for. You can add or close ring systems all you wish - 4-methylaminorex is just a closure of ephedrine, for instance - but to light up the aromatic lipophilic receptor site, it will ideally have to be aromatic and lipophilic. 'n hopefully, benzene, the most powerful agonist of the site on the receptor.
So... what are you trying to do? If you're just desperate to dodge the phenyl ring, cyclopentene and cycloheptene are your best bets, though at a drop in potency. If you're looking to create psychoactive polycyclates with a trippy molecular structure, pick your drug of choice and try to connect parts of it to itself, or extend a charge and turn it back into a ring; I've often thought in unfounded fashion that the 3-cyclate of 4-ethoxyamphetamine might be more interesting than related compounds...
'n if you're just trying to target some specific effect, well... meh, let us know. SARs are documented and old hat; they call them "designer" drugs for a reason, ya know. ;)
Thanks for the reply Joe. I'm quite interested in learning about stuff like this:
Generally speaking, the four things a receptor can check for are positive charge, negative charge, aromaticity, and chargeless lipophilic hydrocarbon; the receptor for THC, for instance, is very sensitive to that last one.
'n different receptors have different spacial preferences for each of these components. The adrenoreceptor involved in decongestion, for instance, prefers its negative charge to be at the 3 and 5 positions on the ring for optimal selectivity, and likes a large hydrophobic substituent on the amine, while the presynaptic noradrenergic receptors appear to prefer negative charge at the 2 and 6 position, and a lump of ammonia much more signifigant than average....
Do you have any literature on the molecular properties (ie charge location) which have consequences in drug design?
PS: What's SAR?
PPS: Thanks much your reply did infact bring the elucidation which I sought.
What's SAR?
Structure-activity relationships.
Do you have any literature on the molecular properties (ie charge location) which have consequences in drug design?
Step 1 :
http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/pihkaltour/pea.gif
http://upload.wikimedia.org/wikipedia/commons/e/e0/Tyramine_structure.png
http://www.biochemistry.bham.ac.uk/osmart/msctox/dopamine.jpg
http://www.3dchem.com/imagesofmolecules/Norepinephrine.gif
http://z.about.com/d/chemistry/1/0/0/b/epinephrine.gif
...form follows function, function follows form...
Step 2 :
http://www.erowid.org/library/books_online/pihkal/pihkal.shtml
...meet the alien probes...
Step 3 or 4 (doesn't matter which) :
You start reading and hoarding shit like...
http://www.studystack.com/studytable-24096
Pay attention to the molecular structure of anything labeled as having preferential binding or selectivity... and pay attention to the effects of every receptor under the sun, and look for drugs which should effect it (e.g. meth/ephedrine/etc and catecholamines), and see which drug has more of what effect.
The other step 3 or 4 :
Look up shit like...
http://profiles.nlm.nih.gov/HH/A/A/B/M/_/hhaabm.pdf
(presumably, only read title)
...and ask yourself, "How could I keep this enzyme from breaking that shit down?" Know all the metabolic points, young padawan.
-
...'n with enough reading, you'll end up bumping into all kinds of other shit, which falls more under "scads of vital miscellaneous trivia" than specific subdisciplines such as 3 and 4 which comprise the bulk of SAR research...
...but just #1 alone should allow you to do a lot of just looking at a molecule and having a vague idea what it does - being able to look at synephrine (http://www.itmonline.org/image/Syn1.JPG), for instance, and forming an educated guess on questions such as "is this a fucktardedly-lethal cardiotoxin with secondary adrenoreceptive activity?"
(if you're not sure, look at the images in #1 again. If that doesn't help, read up on the respective compounds quite a lot).
'n after these, there are other drug targets - transporters, peptidase inhibitors, and the like, for further magic - MDMA, for instance, is primarily a serotonin reuptake inverter and aminopeptidase inhibitor; its direct receptor action, noteable in MDA, is reduced at most receptors by the methyl group until it is only really noticeable in overdose, and then only in a sea of serotonin syndrome...
...but for the most part, the course of study above should suffice for drawing pretty molecular diagrams on the basis of "what do I want it to do, how specific do I want it to be, how potent should it be, and how long do I want it to last."
Whether or not it works like it should is always a mystery, but it's the best guess science has on intelligent design. ;)
FullMetalJacket
2008-06-18, 12:16
I love this forum.
stateofhack
2008-06-18, 15:04
I love this forum.
nah you love JoePedo ;)
And those post above me are more then interesting, an excellent read, although i do not understand it all, but still :)
You're a legit poster usually but why do you post this in every thread?
Why you want to know WHY? because I was was'nt I ? Just stating a fact thats all carry on