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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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MrM301, the article you quoted is talking about the enteral nervous system, not the central nervous system. The GI tract has a large neuronal network that can act independent from the brain for digestive processes. That quote is basically saying both endogenous and exogenous opioid agonist affect nearly all pathways involved in proper function thus leading to constipation. Your thoughts on endorphins and enkephalins stimulating GI motility are incorrect. They do exactly the opposite within the enteric nervous system.

I imagine the brain has some involvement, as it does on every organ system, but the natural opioids in the CNS would still most like have an inhibitory effect on motility, fluid secretion etc. It is just not as clear on how much they effect the GI tract.
 
Why does time go by faster when you're on a goodly dose of (meth)amphetamine?
 
What is delta-FosB exactly and what does it do, such as in response to methamphetamine administration?
 
Anyone got any information on beta carboxylate amphetamine? If it has similar pharmacology to either methylphenidate or amphetamine?

Also on this Wikipedia page it says serotonergic indane amphetamines are non neurotoxic because the methyl group can't form free radicals like in open chain counterparts. I searched the net for more detail on this but couldn't find any papers. Anyone know of any?

How are rats trained to discriminate a drug from saline?

Finally, could anyone speculate on the activity of tetralin and indane derivatives of mephedrone?
 
sekio said:
Wikipedia has a pretty good writeup.
Click to expand...

Thanks, sekio. I thought it was a good writeup as well. Oh well, I guess I need some sodium butyrate:

butyrate.png


Or a viral delta-JunD expression increasing vector; however, both of these phosphorylated delta-FosB reducers would seem to me to be capable of possibly inducing a whole plethora of malevolent unintended consequences such as anhedonia, adverse sexual side effects, or who knows what else.

Also, it would be scary even if they do work with no serious side effects because LE or rehab or family members might start forcing addicts to undergo treatment which many of us don't want. I mean, I think I like having elevated delta-FosB for the most part and think it is a good thing to have as long as harm reduction is employed.

aced126,

You don't want beta-carboxylate-amphetamine. You want beta-carbomethoxy-amphetamine:

1-carbomethoxy-1-phenyl-2-amino-propane.png


It crosses the BBB much better. Its pharmacology is unknown to my knowledge, but I would bet money that it is, in fact, a psychostimulant. Of course, I might lose that bet, but c'est la vie!!!

Que sera, sera! Whatever will be, will be. The future's not ours to see. Que sera, sera!
 
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Is that why ritalinic acid is inactive? What if the carboxylate was administered directly into the brain? Would it be efficacious?
 
aced126 said:
Is that why ritalinic acid is inactive? What if the carboxylate was administered directly into the brain? Would it be efficacious?
Click to expand...

Yes and possibly yes, but in the case of the possibly yes, injecting beta-carboxylate amphetamine directly into the brain would be extremely hard to do without overdosing because when a drug is directly injected into the brain it is something like 140x stronger on a weight basis than usual, and it is likely that beta-carboxylate amphetamine and beta-carbomethoxy amphetamine have somewhat different, mainly subjective effects because, after all, they have slightly different chemical structures. Still, I would venture that both are active though likely not identical in terms of effects; the carboxylate is just a lot harder to safely and effectively administer.
 
What other roles would the carbomethoxy group play other than making the molecule more polar? Would, say, bcm-amph enter dopaminergic neurons at all? I heard ritalin doesn't actually cause vesicular dopamine release into the cytosol but rather just blocks the reuptake pump. Would bcm-amph do the same? I'd guess so.

What are the fundamental differences between just a normal membrane say in the GIT versus the BBB, in terms of molecules being able to diffuse through. I understand there are tight junctions in the BBB, and also that some molecules can pass through normal membranes through endocytosis etc which can't happen in the BBB. But what I'm asking is if a molecule is lipophilic enough to diffuse through the GIT into the blood because it is lipophilic enough to do so, then what's to stop it from diffusing across the BBB?

Edit: Just realised cocaine does have an effect on VMAT. So is the only difference in mechanism of amphetamine and cocaine that cocaine isn't a substrate of TAAR? Also, would a molecule that induces more exocytosis of monoamine vesicles not be neurotoxic? It seems that cytosol is no man's land for monoamines, hence the function of VMAT itself.

Furthermore, I'm finding it hard to believe that a molecule can literally make the transporter work in reverse. I can get to grips with conformational changes (although I will probably never understand the chemistry behind it), but normally since it is such a complex biological mechanism I'd expect it to have a function. Haemoglobin undergoes conformational changes for a biological reason. What is the reason for the ability of DAT or SERT to flip itself when bound to some molecules?

Is there any literature where researchers provide a reaction mechanism for a very simple (or not so simple) protein of probably few amino acids undergoing a conformational change when bound to a substrate?
 
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What are the challenges to crystallizing DAT with covalent ligands in place so that an exact structure for the transporter can be determined?
 
Neurobiology is not my expertise, although I have formally studied it. I have a degree in Chemistry, instead, and mainly just study drugs' structures, classes, and subjective effects to come up with "random," new molecular structures, so I can't answer all your questions other than to say if a molecule has more than 2 or 3 hydroxyls or even one or two carboxyls, then that is enough polarity to negatively impact its crossing of the blood brain barrier. To my limited Biology knowledge, hydrophobicity is not a requirement for a molecule to enter the body through the gastrointestinal tract, if that's what you were referring to. It is, however, for a drug to enter the brain by crossing the BBB. I take neurobiology/chemistry/pharmacology with a grain of salt in many cases and often learn more from reading a trip report and a structure than a table of values of a drug's effects on various neurotransmitter subunit binding affinities.
 
aced126 said:
What other roles would the carbomethoxy group play other than making the molecule more polar? Would, say, bcm-amph enter dopaminergic neurons at all? I heard ritalin doesn't actually cause vesicular dopamine release into the cytosol but rather just blocks the reuptake pump. Would bcm-amph do the same? I'd guess so.

What are the fundamental differences between just a normal membrane say in the GIT versus the BBB, in terms of molecules being able to diffuse through. I understand there are tight junctions in the BBB, and also that some molecules can pass through normal membranes through endocytosis etc which can't happen in the BBB. But what I'm asking is if a molecule is lipophilic enough to diffuse through the GIT into the blood because it is lipophilic enough to do so, then what's to stop it from diffusing across the BBB?

Edit: Just realised cocaine does have an effect on VMAT. So is the only difference in mechanism of amphetamine and cocaine that cocaine isn't a substrate of TAAR? Also, would a molecule that induces more exocytosis of monoamine vesicles not be neurotoxic? It seems that cytosol is no man's land for monoamines, hence the function of VMAT itself.

Furthermore, I'm finding it hard to believe that a molecule can literally make the transporter work in reverse. I can get to grips with conformational changes (although I will probably never understand the chemistry behind it), but normally since it is such a complex biological mechanism I'd expect it to have a function. Haemoglobin undergoes conformational changes for a biological reason. What is the reason for the ability of DAT or SERT to flip itself when bound to some molecules?

Is there any literature where researchers provide a reaction mechanism for a very simple (or not so simple) protein of probably few amino acids undergoing a conformational change when bound to a substrate?
Click to expand...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729543/

Here is a good summary of the structure and mechanism of monoamine transporters and the phosphorylation sites that modulate their function.

In short, they use an "alternate access" process where Na+ co transport fuels conformational change between inward-facing and outward-facing positions.
Beyond this basic functionality there's several proposed/involved mechanisms for amphetamine induced reverse transport: amph influx via DAT increases the number of inward facing DAT, amph-induced increaes in intracellular sodium would drive reverse transport, and amph also appears to cause a burst/channel-like function in DAT releasing a quanta of DA.

Keep in mind how similar amphetamine is to endogenous phenethylamine--it behaves essentially identically except for its resistance to MAO. So any functionality of AMPH at monoamine transporters isn't really an accident of chemistry and nature, but rather a utilization of existing functional mechanisms normally driven by endogenous phenethylamine.
 
Do relevant substitutions to amphetamine like 3,4-methylenedioxy, 4-chloro etc actually reduce the affinity at DAT and other dopamine releasing mechanisms? You'd need around 150mg of MDMA for good recreational effects, but for the amphetamine counterpart you need significantly less. Obviously amphetamine has very little serotonergic properties.
 
Do benzodiazepines not get sold as salts because they already have a pretty good bioavailability as it is? It is my understanding that drugs get sold as salts to be better absorbed (and more stable).

I mean there are plenty of nitrogens there that could be protonated so it's not the same case as say THC.

I wondered if there was something funny with the nitrogens in the diazepine/triazolo rings so they didn't readily donated electrons or something but i think midazolam is in fact available as the HCl salt. Any particular reasons why midazolam in particular is salted? When they IV diazepam why instead of using PEG as vehicle (which causes metabolic acidosis or smth, the reason midazolam HCl is prefered) don't they use diazepam HCl?
 
In acidic solutions protonated benzodiazepines exist in an open-chain form. The triazole ring doesn't take part in protonation in any way (other than impacting basicity of the amine in some way), but I guess imidazo- and triazolobenzodiazepines in open-chain form may be more stable because there is no way they could undergo irreversible hydrolysis while classic benzodiazepines have a carbamoyl moiety which may be further hydrolysed. Perhaps classic benzodiazepines can't be stored under acidic conditions for too long, but that's just a guess.

Nowy_obraz.jpg
 
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What is the rate at which a non charged lipophilic molecule crosses the GIT bilayer?

Is it proportional to the concentration of the molecule itself, or is it something more complicated ?
 
adder,

I hate to be a naysayer with no good source to back up my counterclaim, but I really kind of doubt benzodiazepines spontaneously break open in acidic aqueous media such as the stomach. I know that imines are unstable in aqueous media, but I think the cyclic ones are much more stable. As for which salt the benzos usually are, I think the companies bringing them to market first starting in the 70s or late 60s or whenever it was were lazy and just never really felt the need to list which salt they were using. It's probably usually the fumarate salt or something.

aced126,

I know that peppering one's speech or writing with a good amount of acronyms lends the air of erudition to one's speech or writings, but personally, I generally try to avoid doing so, as technical acronyms often also impede the ability for one's fully formed thought/message to reach one's users' understandings. Case in point, what do you mean by "GIT" exactly? If you mean gastrointestinal tract, then it is a not easily predictable property of a drug that is also drug specific. For example, some drugs are best absorbed on an empty stomach, others (ziprasione) are much better absorbed on a full stomach, and others yet (amphetamines) are well-absorbed with or without food. I mean, I've heard of GIT HER DONE or GIT HER DRUNK, but science acronyms such as the HOMO-LUMO (highest occupied molecular orbital lowest unoccupied molecular orbital) gap just make me laugh, especially when they're in all caps. It's highly DISTRACTING.
 
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As for which salt the benzos usually are, I think the companies bringing them to market first starting in the 70s or late 60s or whenever it was were lazy and just never really felt the need to list which salt they were using. It's probably usually the fumarate salt or something.
Click to expand...

most benzos are sold as freebase, drug labeling laws require the specification of a salt if you're selling a salt (i.e. nobody is allowed to sell dextromethorphan hydrobromide as just 'dextromethorphan', it must be labeled HBr if it is the hydrogen bromide salt... you can't just "get lazy")

i thought most BZDs actually were amides that lacked basic nitrogens which could get protonated with the exception of a few (midazolam)... the imide doesn't pick up a proton like a 'normal' amine does, IIRC
 
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