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

[chompy]

try eating bananas

 

[Hammilton]

Does 4-Methyl-5-phenyl-2-oxazolidinone have any stimulant properties? It's a metabolite of 4-methylaminorex. And readily available.

Quite likely.

 

[ebola?]

Look at their affinity for the receptor to figure out which is a better competitor. If they both bind equivalently (which I doubt) then they would both compete with 5HT equally and you'd get an equal mix of activity theoretically.

Ah. This is what I surmized...but how close together must the binding affinities be for them to be 'equivalent'? How do other factors, like size of dosage, bioavailability from given route of admin, and propensity to cross the BBB factor in?

ebola

 

[nuke]

Ah. This is what I surmized...but how close together must the binding affinities be for them to be 'equivalent'? How do other factors, like size of dosage, bioavailability from given route of admin, and propensity to cross the BBB factor in?

ebola

Okay, back to theory...

You have two compounds, X that has an IC50 of 2mM and Y that has an IC50 of 4mM. Therefore, to get the same amount of displacement of the substrate you would need double the amount of Y as you would X. So if you consumed 1mmol of X and 2mmol of Y, you should get an equal amount of competition in theory. So you can see, the binding affinities should probably be within ± 10% of each other to be considered equivalent (just as a thrown-out there rule). Since such a similarity is generally unlikely, you should easily be able to see who the more competitive compound will be.

To actually figure out the exact concentration in the brain would be tricky. I'm guessing the most reasonable way would be to make a radiolabeled version of the compound and run it against a known control with some sort of imaging like PET. There are calculations for blood barrier penetration but in my opinion they're not extremely accurate and fail to take into account factors such as active transport of the molecule into the brain by amino acid transporters. Another problem is active metabolites that may also play a role in the activity of the compound.

A program to assist in the calculation of BBB penetration via TPSA is here: http://www.daylight.com/meetings/emug00/Ertl/index.html

Once you get into the activity, that's also fairly obfuscated by the fact that despite direct agonist/partial agonist/antagonist/inverse agonist activity there are also downstream modulators of activity which may be targeted by a given compound or its competing compound. For instance, while a molecule may be a substrate for the dopamine transporter and cause dopamine release, however it may also have an affinity for the 5HT1A receptor as an agonist that would cause it attenuate the dopamine release (at least in the striatum). Not to mention other factors like receptor isoforms, which are very common, that could alter the binding cavities of the receptors themselves and therefore modulate the binding affinity of a compound in unpredicatable ways.

There are so many variables involved that to say exactly what to expect from a combination of X and Y is extremely difficult -- probably why Shulgin always said that combinations of drugs should be treated as cautiously as a new drug itself.

 

[permastoned]

Quite likely.

Is this from your steric knowledge/common sense or from personal experience?

 

[nuke]

4FA freebase is a caustic oil. You should be able to recrystallize the 4FA salt by dissolving it in something that is slightly soluble at a high temperature, then chilling it and filtering it.

 

[nasir~]

by dissolving it in something that is slightly soluble at a high temperature.

something like water?

 

[nuke]

Possibly, I don't know much about the solubility. Maybe water and methanol, ethanol, or acetone.

 

[ebola?]

Thanks nuke.
That's the kind of detail that I desired.

edit: in reference to post on binding affinities.

 

[Artificial Emotion]

How do you clean a buchner funnel/filter?

Also, I mixed some tap water with some surgical spirit (ethanol and methanol) which went mily white. What caused this to happen?

 

[nasir~]

Thanks nuke.
That's the kind of detail that I desired.

thanks a lot nuke:D

 

[nasir~]

very soluable in water. instantly.
acetone too

what was (~) the highest concentration you tried?

thanks

 

[almost-]

Does benzobarbital have any recreational properties?

 

[shibireru]

What are the neurochemical/physiologic conditions under which opioid dysphoria is most likely to manifest? Does any of you know from personal experience what substances are like to prime one for such a negative reaction to opioids?

Out of the blue my neurochemistry seems to have changed in such a way that I can't take an opioid without feeling otherworldly despair. I took a small amount of hydrocodone last week and felt a barely noticeable sense of wellbeing, far far less than that dosage would normally induce, and then upped the dose hoping for better, but far from becoming euphoric I was plunged into some of the deepest blackness I have felt in years. Since then I tried several other opioids at various low doses and got nothing but sadness and tearfulness out of them.

Very strange to be sure. I hope this reverses.

 

[Artificial Emotion]

If you filter pod tea with a triple stack of lab filters and then with a 0.2u bottle top Nalgene filter that uses vacuum filtration, only to find that it clogs straight away even after having used the lab filters, what is a good filter to use as an inbetween step so that it doesn't clog? Should one use Celite (diatomaceous earth)?

I've seen lots of different 'types' of diatomaceous earth for sale. Which type is the most appropriate for filtering pod tea?

Also, can you put a buchner funnel (see pic above) in a dishwasher?!

 

[shibireru]

Okay, I gave my question a little more thought and the answer seems to be that my long-term use of phenethylamine has provoked an upregulation of the transcription of the kappa opioid receptor-encoding gene or of the prodynorphin gene in my nucleus accumbens. Additionally, mu-opioid receptor agonists provoke a release of cortisol which in turn has the effect of releasing dynorphin, the principal endogenous agonist of the kappa opioid receptor. A downregulation of D2 receptors and the hypofunctioning of dopaminergic neurons within the pleasure centers of my brain on account of the long-term potentiation of glutamatergic projections into said pleasure centers are both also distinct possibilities.

Memantine doesn't seem to help.

Anyone want me for a guinea pig? I wouldn't mind testing out some of the kappa-opioid receptor antagonists you've synthesized...

 

[shibireru]

P.S. I would be very interested in hearing the results of one of you coke heads experimenting with a combination of a kappa opioid receptor antagonist, like buprenorphine, memantine, and cocaine. Maybe you could throw in a low dose of amisulpride, too, if you should happen to be feeling especially bold at the time of experimentation. If that's not one of the most pleasureful experiences of your life, I'll give you - well I don't have much money at all - so $100 is about the absolute maximum that I could afford (and that with a lot of sacrifice.) If you're not alive, I'll have the $100 buried with your corpse.

 

[Enkidu]

Also, can you put a buchner funnel (see pic above) in a dishwasher?!

That's not a buchner funnel, it's a fritted filter. The glassware will hold up find in the dishwasher.

 

[ebola?]

Okay, I gave my question a little more thought and the answer seems to be that my long-term use of phenethylamine has provoked an upregulation of the transcription of the kappa opioid receptor-encoding gene or of the prodynorphin gene in my nucleus accumbens.

I'd like to see the information on which you're basing this hypothesis.

ebola

 

[shibireru]

I'd like to see the information on which you're basing this hypothesis.

ebola

http://www.ncbi.nlm.nih.gov/pubmed/17055175

Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS.

It has been shown that chronic cocaine increases prodynorphin mRNA in the caudate putamen and decreases it in the hypothalamus. In addition, treatment with a kappa-opioid receptor agonist produced the opposite effect on prodynorphin gene expression in these brain regions and also evoked a decrease in the hippocampus. It is already known that kappa-opioid receptor agonists decrease the development of sensitization to some of the behavioral effects of cocaine. The serotonin system has also been shown to regulate dynorphin gene expression and a continuous infusion of fluoxetine induced prodynorphin gene expression in the same pattern as the kappa-opioid agonist (+)(5a,7a,8b)-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U-69593) in the brain regions investigated. It is interesting to note that treatment with a continuous infusion of cocaine produced different effects on this parameter. To determine whether serotonin plays a role in the regulation of prodynorphin mRNA by kappa-opioid agonists or cocaine, rats were treated with the serotonin depleter parachloroamphetamine (PCA). Beginning 24 h later, rats were treated with the selective kappa-opioid agonist U-69593 for 5 days or continuously with cocaine for 7 days and prodynorphin mRNA was measured. Prodynorphin mRNA was decreased significantly in the hypothalamus, caudate putamen, and hippocampus of rats treated with a single injection of PCA. Subsequent to PCA administration the effects of U-69593 or cocaine on prodynorphin mRNA were differentially affected across brain regions. Prodynorphin gene expression was still increased by U-69593 treatment in the hypothalamus and decreased in the caudate putamen. Cocaine treatment still produced a decrease in this parameter in the hypothalamus and an increase in the caudate putamen. In contrast, in the hippocampus, the decrease in prodynorphin mRNA produced by U-69593 was no longer evident after PCA and cocaine, which previously had no effect, now increased it in the serotonin-depleted group. These findings suggest that serotonin is necessary to maintain normal levels of dynorphin mRNA in all of the investigated brain areas and that the regulation of prodynorphin mRNA expression by chronic treatment with a kappa-opioid receptor agonist or cocaine requires serotonin in the hippocampus, but not in the hypothalamus or caudate putamen.

http://www.sciencedirect.com/scienc...serid=10&md5=6e5784c6d7daaff57d281288cabff9f2

Chronic prenatal cocaine treatment down-regulates μ-opioid receptor mRNA expression in the brain of fetal Rhesus Macaque.

Ribonuclease protection assays (RPA) were performed to quantify μ-opioid receptor mRNA expression in specific brain regions of day 70 Rhesus Macaque fetuses that were exposed to cocaine (3 mg/kg) or saline from days 22–70 of gestation. The content of μ-receptor mRNA was high in the diencephalon and moderate in the mesencephalon. In contrast, μ-receptor mRNA was lightly expressed in areas such as the frontal cortex, striatum and the temporal lobe. The content of μ-opioid receptor mRNA was significantly higher in the diencephalon than in other brain regions (P<0.001; n=4). Cocaine exposure significantly decreased the expression of μ-receptor mRNA in the fetal diencephalon (P<0.05; n=4 in each group). Our data would indicate that prolonged gestational cocaine exposure causes μ-opioid receptor mRNA down-regulation in specific brain regions of the fetus.

http://www.ncbi.nlm.nih.gov/pubmed/16001119

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats.

RATIONALE: Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake. OBJECTIVES: To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP. METHODS: Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg(-1)) while ethanol intake was monitored. RESULTS: A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline. CONCLUSIONS: Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.

http://www.ncbi.nlm.nih.gov/pubmed/9435173

[Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study.

Mu and kappa opioid agonists are known to produce different, and sometimes opposite, effects on several pharmacological and behavioral measures. However, whether kappa agonists can be used to antagonize the reinforcing and putative dopamine (DA)-releasing properties of a mu agonist such as heroin is unclear. With the use of the high temporal and spatial resolution of in vivo fast-cyclic voltammetry to measure changes in extracellular DA in the nucleus accumbens (NAcc), we observed (1) dose-dependent increases in DA in the NAcc during heroin self-administration (SA), (2) that coadministration of the kappa agonist U50,488H with heroin or intracerebroventricular dynorphin A pretreatment significantly depressed the heroin-stimulated DA release during SA, where U50,488H alone inhibited the basal DA release in the NAcc, (3) that coadministration of low-dose U50,488H or dynorphin A significantly increased heroin SA behavior, whereas high-dose U50,488H, which alone did not support SA behavior, reduced or completely blocked heroin SA and (4) that nor-binaltorphimine dihydrochloride (a selective kappa receptor antagonist) potentiated DA release in the NAcc and modestly decreased heroin SA. Taken together, these data suggest that endogenous kappa receptor activation can inhibit mu agonist-induced activation of the mesolimbic DA pathway, which may in turn depress heroin-induced reinforcement.

http://www.ncbi.nlm.nih.gov/pubmed/10391475

The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat.

The present study was carried out to evaluate the effect of morphine, cocaine and ethanol on the density of opioid receptors in the nucleus accumbens and striatum of rat brain. The animals were injected i.p. with morphine in a single dose 20 mg/kg, or twice daily for 10 days in increasing doses of 20-100 mg/kg. Cocaine was administered in a dose of 60 mg/kg/day following the "binge" paradigm, every hour for 3 h, one day (single treatment) or five days (chronic treatment). Ethanol was administered in drinking water at increasing concentrations of 1-6% v/v, for one month. As shown by receptor autoradiography, single morphine and cocaine administration did not influence the binding density of the selective ligand of delta2 receptors [3H]Ile5,6deltorphin b, but single administration of cocaine decreased binding density of a highly selective antagonist of delta receptors, [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH. Repeated morphine administration decreased the receptor density after both ligands of the delta receptor in the nucleus accumbens after 3, 24 and 48 h, and in the striatum after 24 and 48 h. The density of [3H]Ile5,6deltorphin b binding remained unchanged in both structures following repeated cocaine administration. After repeated cocaine administration either no changes (3 h) or a decrease in the binding of [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH in the nucleus accumbens and striatum were observed after 24 and 48 h. Ethanol did not influence the binding density of [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH and [3H]Ile5,6deltorphin b in the nucleus accumbens and striatum at any time-point studied. In the nucleus accumbens and striatum, no changes were found in the binding density of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol following single or repeated morphine administration. At 3 h after single or repeated "binge" cocaine administration, the binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol was not changed in either structure, but after 24 h the density of mu opioid receptors was decreased in both structures. Ethanol given to rats in drinking water decreased the binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol at the time of exposure to ethanol, yet in the nucleus accumbens only. Ethanol withdrawal decreased the density of the mu receptor in both structures after 24, 48 and 96 h. The above data indicate that repeated administration of morphine evokes a long-lasting down-regulation of the density of delta1 and delta2 opioid receptors, whereas cocaine affects in a similar way only the delta1 subtype in the nucleus accumbens, and to a lesser extent in the striatum. A long-term intake of ethanol solution down-regulates mu opioid receptors in both structures, but has no effect on any type of delta receptors. Thus changes in the particular opioid receptor depend on the type of drug used. Furthermore, the most profound changes are observed after late withdrawal, which may play some role in maintaining the state of dependence.