The Large and Nifty Not-quite-advanced Drug Chemistry, Pharmacology and More Thread

[Hammilton]

Because they bind to and directly effect GABA-A receptors. FAAH inhibitors slow the metabolism of the endogenous substances that bind to the CB1 and 2 receptors resulting in increased concentration. RIMAs slow the metabolism of monoamines (5HT, NE, and to a lesser extent, DA), resulting in increased concentration.

Benzos have an activity that's entirely unrelated to these two; where FAAH inhibitors and RIMAs and MAOIs in general do basically the same thing with two different classes of drugs, benzos exert their effects directly on the receptor. That's why they're not relevant here.

 

[Enkidu]

I'm still talking about positive modulation of the CB1 receptors. Benzodiazepines are somewhat more relevant to that discussion.

 

[shibireru]

I have little experience with these, but it seems more likely that they'll produce antidepressant and anxiolytic effects (or maybe not the latter? not a common cannabinoid effect) but probably won't result in cannabimimetic-type effects, basically the way RIMA's don't produce MDMA or even Fenfluramine type effects.

Why is that anyways? Simply because this sort of activity doesn't strongly conduce to disgorgement of neurotransmitters into the synapse?

I think you mentioned once that you had injected some endocannabinoids and said that they had had no noticeable effect. This is even more interesting. What reasonable hypothesis would account for this? Is FAAH's catabolic activity comparable to MAO's? Or does it have to do with the nature of the conformational change that endocannabinoids produce at the CB1 receptor? That the pharmacodynamic activity of exocannabinoids like THC isn't well characterized yet and that they have affinities for other receptors as well?

 

[Hammilton]

Well, it's difficult to say, but it may be somewhat similar to that seen with monoamines, where just adding SE doesn't result in MDMA or psychedelic effects, adding DA doesn't result in amphetamine or cocaine like effects (though there is some very minimal evidence that l-dopa can be somewhat recreational, though we are talking pretty minimal, at least so far).

Or does it have to do with the nature of the conformational change that endocannabinoids produce at the CB1 receptor?

I assume that it is related to this, though in animal models, they seem to produce changes somewhat related to that seen with exogenous cannabinoids. Perhaps there are other endogenous cannabinoids that could do this, I'm not really sure.

Is FAAH's catabolic activity comparable to MAO's?

I'd have to look into this more, but there are some pretty major differences between these. It seems that all of the MAOIs are either irreversible (or they're reversible, but the concentrations required to reverse aren't clinically relevant for most part, though I'm sure that this is not entirely true, but seems to be for the most commonly used RIMAs, at least those I'm familiar with). From what I know of FAAH inhibitors, they don't inhibit FAAH to nearly the extent that MAOIs do MAO. It seems more comparable to other enzyme inhibitors like those used with opioid enhancement.

This might be entirely wrong, I've read very little on the subject and this is mostly the impression I've gotten.

But really, one trial isn't worth much and probably shouldn't be used for any sort of generalization. There'll be people given fair doses of morphine who don't notice an effect either, and I tend to always expect nothing to happen with new new things. All of this said, I have heard another report that had the same results (without the headache).

Ham

I'm still talking about positive modulation of the CB1 receptors. Benzodiazepines are somewhat more relevant to that discussion.

Ah, I see. I don't know. I'm not even aware of any, honestly.

 

[Sturnam]

Well, since I think my question got lost in the suicide debate, here it is again.

This is the quote for TiHKAL tryptamine entry:

Tryptophan, a natural and nutritionally essential amino-acid, is a centrally active intoxicant and sleep-provider in man. It is converted metabolically to tryptamine which is a little bit psychedelic. When administered with methionine (another amino-acid known to methylate things) it produces methylated tryptamines, the two best studied being N-methyltryptamine (NMT) and N,N-dimethyltryptamine (DMT).

Is he saying that tryptophan + methionine = methylated tryptamines in vivo? Does anyone know if there is any scientific articles about this, or if he's just guessing, or extrapolating from in vitro?

 

[Hammilton]

No idea, but I was much more interested in the "centrally active intoxicant" part.

Has there been any reports at erowid or bluelight of a recreational tryptophan overdose?

 

[hamhurricane]

quick worm question?

there was a study linked off "the dark side" which discussed an opioid containing silk worm, i found the journal article but i remember it saying the worms contained ß-endorphin and Leu-enkephalin, was i reading it right? there was nothing novel in the worms just two endogenous opioids?

 

[MurphyClox]

@Sturnam: Methionine alone is NOT a methylating agent. One needs rather S-adenosyl-methionine, which won't methylate anything without the help of the proper enzyme though. Looking at the biochemical significance of methionine, I doubt that the combo Trp + Met will yield a significant amount of DMT resp. NMT in vivo. No chance!

- Murphy

 

[TheLastAxon]

Is it likely that Methylone could form into toxic metabolites that would result in reactive quinone species? I understand that it's lower SE/DA activity would mean an overall lower chance of toxicity, but I'm wondering about the potential for toxicity from methylone alone if combined with amphetamine.

 

[mr.dopeman]

advanced THC and other cannabinoids solubility

Does anyone know the solubility of THC and other cannibinoids in solvents such as ethanol, isopropyl alcohol, and acetone. And specifically at spefcific temepratures. Are Thc and any other of the cannibinoids insoluble in any of those solvents at a temeprature achivable in a freezer?

 

[leungkachong]

Well, it's difficult to say, but it may be somewhat similar to that seen with monoamines, where just adding SE doesn't result in MDMA or psychedelic effects, adding DA doesn't result in amphetamine or cocaine like effects (though there is some very minimal evidence that l-dopa can be somewhat recreational, though we are talking pretty minimal, at least so far).

In the case of l-dopa... it appears that the mesolimbic effect is so weak that the brain essentially mistakes the discrepancy between expected reward and actual reward to another pleasurable stimulus, rather than the l-dopa itself. I believe you were probably referring to dopamine dysregulation syndrome (or "why the l-dopa'd up parkinson's patient is using his limited motor capacity to hump your leg and gamble").

Actually, I even feel uncomfortable describing it in this manner. Rip out the VTA or the Nuc.Acc.(well, pull out the Talairach atlas and perform some stereotactic surgery), and give our furry rodent friends an all access pass to some DA-ergic drugs... and they'll still go for them (ie - they still are re-inforcing, and therefore likely 'pleasurable'). What they WON'T do is get off their ass and perform a task to get the drugs.

That's evidence for at least a single dissociation between 'liking' and 'wanting'. And any drug addict knows that they aren't always taking the drug cuz they 'like' it, they just want it. The reward pathway is probably more accurately described as the 'desire pathway'. And in that case, l-dopa does represent DAergic activity just as well as amphetamine (using one of your examples)... as it allows us to distinguish OUTSIDE cues as what we want, rather than the mutant-weirdo DA-wannabe amphetamine.

ps- I love talking about science like that, but I don't know if it makes it harder to understand... if it is, I'll go back to my boring formal descriptions.

 

[blau1005]

Not sure if this is the thread for it, but it doesn't deserve it's own thread. This may be better placed in the GFJ FAQ, but I'm looking for some specific 'ADD style' answers If this isn't the spot please let me know where to ask this stuff.

Mr Blonde suggested that grapefruit juice may inhibit CYP2D6 as well as CYP3A4 and a bunch of other enzymes. He linked to this article. I don't have access to that service so can't read the full article but have a few questions about the abstract.

1. What does this mean: "All four furanocoumarins clearly inhibited CYP3A4-catalyzed nifedipine oxidation in concentration- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4."

2. "Inhibitor concentration required for half-maximal rate of inactivation (KI) values for bergamottin, DHB, GF-I-1, and GF-I-4 were calculated, respectively, as 40.00, 5.56, 0.31, and 0.13 μM, whereas similar values were observed on their inactivation rate constant at infinite concentration of inhibitor (kinact, 0.05–0.08 min−1)."
What is the half-maximal rate of inactivation? Does this mean the enzyme's efficacy was reduced to half?

3. Any other information regarding furanocoumarins inhibiting CYP2D6? The feeling seems to be that GFJ potentiates codeine but not to any great extent. I am wondering whether the CYP2D6 inhibition could be responsible for this; ie it inhibits CYP3A4 which increase efficacy of the codeine, but the inhibition of CYP2D6 means that this potentiating action is not felt as much. And yeah this could be due to users consuming GFJ with low levels of the furanocoumarins but even those using fresh juice don't report any great response. Also how does the ceiling effect come in to play here?

Cheers guys!

 

[Sturnam]

^^^ for #2:
yes. They're just giving the IC50. means that 50% of the enzyme is inihibited. it's just a standard unit of sciencey stuff.

and #3, GFJ does NOT potentiate codeine. it fact, it does the opposite. codeine is a prodrug that is metabolized to morphine through CYP2D6, so if you inhibit that, then you don't get any morphine.

 

[Black]

#1 essentially means that the data fits together. if you measure inhibition of enzymes that is not concentration dependent chances are you have fucked up or are measuring something different than you intended...
if the inhibition is proportional to the concentration of the supposed inhibitor you sort of know that the substance you tested is the one responsible.

 

[ebola?]

To return to the cathinone derivative question, does methylone cause primarily dopaminergic reuptake inhibition or release via transporter reversal? I have heard conflicting reports...and should probably get off my ass and look up the journal article.

ebola

 

[ebola?]

Another question: I heard someone in here argue that some people experience attenuation of dopaminergic releasers' effects when on selegiline because selegiline itself interferes with DA transporter reversal. By which mechanisms could this be possible?

ebola

 

[Coolio]

Maybe it's the l-meth and l-amph metabolites? The DA transporter reversal seen with amphetamine was with racemic right?

 

[any major dude]

Don't know if this deserves its own thread or not, but anyway... I know some isoquinolines have an inhibitory effect on acetylcholinesterase, and some may affect MAO A & B. I can see how the latter would cause otherwise inactive alkaloids in various species of cacti to be active, but I haven't been able to find much info on which isoquinolines are in trichocereus cacti, or by which mechanism they may cause activity. Anyone know much about this? or know of a study or paper to direct me to?

 

[Sturnam]

ebola?

Found this article.

Methcathinone, the benzylic ketone analog of methamphetamine (MA), and methylone, the benzylic ketone analog of 3,4-methylenedioxymethamphetamine (MDMA), were synthesized and tested for their abilities to inhibit monoamine uptake in vitro. Methcathinone and methylone were threefold less potent than MA or MDMA at inhibiting [3H]5-HT uptake into human platelets, with IC50's of 31.4 ± 7.3 uM and 5.8 ± 0.7 uM, respectively. In C6 glial cells stably expressing the rat dopamine transporter, methcathinone and methylone were similar in potency to MA and MDMA, with IC50's for [3H]DA uptake of 0.36 ± 0.06 uM and 0.82 ± 0.17 uM, respectively. Methcathinone and methylone were also similar in potency to MA and MDMA in C6 cells expressing the human norepinephrine transporter, with IC50's for [3H]NE accumulation of 0.51 ± 0.10 uM and 1.2 ± 0.1 uM, respectively. The benzylic ketone moiety of methcathinone and methylone had a large (tenfold) negative impact on the abilities of these drugs to inhibit the vesicular monoamine transporter (VMAT2) compared to MA and MDMA. In VMAT2-containing bovine chromaffin granules, the IC50's for [3H]5-HT uptake were 103 ± 15 uM for methcathinone and 125 ± 16 uM for methylone. These results indicate that methcathinone and methylone are potent and selective inhibitors of plasma membrane catecholamine reuptake transporters, with more modest effects at the serotonin reuptake transporter. These drugs are essentially inactive at the vesicular monoamine transporter.

From here:
NV Cozzi, MK Sievert, AT Shulgin, P Jacob III, AE Ruoho. Methcathinone and 2 methylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (methylone) selectively inhibit plasma membrane catecholamine reuptake transporters. Soc. Neurosci. Abs., 24, 341.8 (1998)

 

[blau1005]

GFJ does NOT potentiate codeine. it fact, it does the opposite. codeine is a prodrug that is metabolized to morphine through CYP2D6, so if you inhibit that, then you don't get any morphine.

Thanks for the answers. This is kind of what I was getting at. GFJ does inhibit CYP3A4, increasing the efficacy of the morphine (that comes from the codeine). However because CYP2D6 is also inhibited, does this mean that GJF has zero net effect on the drug's action? Or does it inhibit CYP2D6 less than CYP3A4, meaning that using GFJ would overall add to the effects?

Cheers