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

[shibireru]

http://www.ncbi.nlm.nih.gov/pubmed/18184783

The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.

Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a kappa-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2 receptor antagonist antisauvigine-30, but not by the CRF1 receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2 receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes kappa-receptor antagonists as promising therapeutics.

http://jpet.aspetjournals.org/cgi/content/full/292/2/803

Hydrocodone has an affinity (Ki) for the human µ-receptor of 36.4 nM, which is 28 and 20 times greater than its affinity for the delta -opioid and kappa -opioid receptors, respectively (Maguire et al., 1993).

To summarize the salient and relevant information of these studies:

Agonism of KORs = antagonism of MORs, DORs, and D2 receptors and to the sensitization and upregulation thereof as well as, of course, to the desensitization and downregulation of the KOR and prodynorphin.

Agonism of MORs = downstream activation of D2 receptors and inhibition of KORs, and all the other obvious crap that I needn't explain at all.

D2 agonism = downregulation of DORs, possibly MORs, and upregulation of KORs and prodynorphin mRNA transcription.


Being that I have long been extremely depressed (i.e. paucity or densensitization of MORs, DORs, and/or D2 receptors); that I have abused phenylethylamine on a long-term basis (meaning further downregulation of D2 receptors, DORs, MORs, and upregulation of KORs, and prodynorphin expression); and finally that hydrocodone or one of its metabolites has some considerable affinity for KORs, especially when there is a paucity of MORs and DORs, it is only to be expected that in higher doses hydrocodone should cause extreme dysphoria and depersonalization as it did to me and that in lower doses it would produce only the mildest euphoria, which, again, is exactly what happened.

I further speculate that buprenorphine, a kappa opioid receptor antagonist, and a (partial) mu opioid receptor agonist would be highly apt to produce euphoria in me and very unlikely to produce dysphoria.

I also wonder whether or not it would be beneficial for me to undertake long-term low-dose Salvia Divinorum therapy or low-dose Naltrexone/Naloxone therapy, as horrific as either undertaking should be until the desired upregulation and the desired downregulation occurred.

http://www.ncbi.nlm.nih.gov/pubmed/15464069

Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist.

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.

http://www.ncbi.nlm.nih.gov/pubmed/17702750

Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase.

Norbinaltorphimine (NorBNI), guanidinonaltrindole, and atrans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine (JDTic) are selective kappa opioid receptor (KOR) antagonists having very long durations of action in vivo despite binding non-covalently in vitro and having only moderately high affinities. Consistent with this, we found that antagonist treatment significantly reduced the subsequent analgesic response of mice to the KOR agonist U50,488 in the tail-withdrawal assay for 14-21 days. Receptor protection assays were designed to distinguish between possible explanations for this anomalous effect, and we found that mice pretreated with the readily reversible opioid antagonists naloxone or buprenorphine before norBNI responded strongly in the tail-flick analgesia assay to a subsequent challenge with U50,488 1 week later. Protection by a rapidly cleared reagent indicates that norBNI did not persist at the site of action. In vitro binding of [(3)H]U69,593 to KOR showed that K(d) and Bmax values were not significantly affected by prior in vivo norBNI exposure, indicating that the agonist binding site was intact. Consistent with the concept that the long-lasting effects might be caused by a functional disruption of KOR signaling, both norBNI and JDTic were found to stimulate c-Jun N-terminal kinase (JNK) phosphorylation in HEK293 cells expressing KOR-GFP but not in untransfected cells. Similarly, norBNI increased phospho-JNK in both the striatum and spinal cord in wild type mice but not in KOR knock-out mice. Pretreatment of mice with the JNK inhibitor SP600125 before norBNI attenuated the long acting antagonism. Together, these results suggest that the long duration KOR antagonists disrupt KOR signaling by activating JNK.

http://www.ncbi.nlm.nih.gov/pubmed/16184376

Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.

RATIONALE: Stress and depression have been linked to relapse of cocaine abuse. Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties. OBJECTIVES: Our objective was to determine whether the potent and selective KOR antagonist, (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST). METHODS: Male Long-Evans hooded rats were trained to lever-press, reinforced with 0.5 mg/kg i.v. infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered i.g. to separate groups of 12 rats. Twenty four hours later, the rats were given 15 min of intermittent footshock (0.87 mA, 0.5 s activation time, average inter-activation interval of 40 s) or a 17-mg/kg i.p. administration of cocaine prime followed by a 2-h reinstatement test session. JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, s.c.), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity. In the FST, male Sprague-Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 0.3, 1, 3, or 10 mg/kg, injected s.c. 23 h before), or desipramine (5.6, 10, or 17 mg/kg, injected i.p. 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min. RESULTS: The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis. In contrast, JDTic did not affect cocaine-prime-induced reinstatement. Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine. CONCLUSIONS: Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both.

I wonder whether or not Ketamine is a kappa opioid receptor antagonist. According to the SAR paradigm, it's not entirely impossible. It may also be that it is an inducer of c-Jun N-terminal kinases as JDTic is. This may be shallow and fallacious reasoning, but it seems attractive to conclude that there is some considerable similarity between the pharmacodynamics of ketamine and KOR antagonists based on the fact that they both have the peculiar property of being able to produce an abatement of depression that endures well after the substances have been metabolized and excreted from the body. Weak support for this hypothesis comes in the fact that the (partial) NMDA antagonist Memantine does not have any antidepressant effect and certainly not one that endures for weeks after a single dose. So what's the difference between Memantine and Ketamine? Simply that Memantine only partially antagonizes the NMDA receptor? Is that the ONLY reason it doesn't have an antidepressant effect at ANY dose?

 

[shibireru]

And so I repeat my offer to be used as a guinea pig. I would be so glad to give a kappa opioid receptor antagonist a try. I would give my fucking left arm, in fact. I can't stand to feel this way even one second longer. I want to fucking enjoy life again - for the first time in years. Someone help me, please.

 

[ebola?]

Wow. Very intriguing. Thanks.

 

[Is it Friday yet?]

Cocktails or not?

Right - I have Mephedrone, Butylone and some Methylone on the way.
Could someone give Noob advice on cocktails eg Don't or if do in what amount and how? I have heard that the right mix is the shizz!
I'm sure this has been discussed before and if there is a thread could someone guide me.

ps this is after I take a holiday from meph. planecrash

Moderators please bump to thread if req.

 

[ebola?]

this is unexplored territory, and mephedrone seems pretty dangerous, so I'd tread w/ caution if at all. Perhaps beginning with 150-200 mg of substances total. These also don't sound like the best combos in terms of fx. All of these compounds are overly stimulating to begin with, so I don't see how they'd be good complements.

ebola

 

[Is it Friday yet?]

Thanks ebola
After Saturday nights little excursion to the darkside I will be treating Mephedrone with a little more respect anyway, but as always in search of repeating that 1st true MDMA experience, I had heard and seen for sale a mixture called 'Bubbles' (don't think this is trade name) and sorry if this violates BLUA. As I understand this is a mix of Methylone and Mephedrone??And as such the buzz is even closer to MDMA
Anything further ppl???

 

[nuke]

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?

That looks like a crucible, not a Buchner funnel. You can clean a crucible by soaking it in a 70% EtOH solution with a high concentration of sodium hydroxide and then rinsing it off with distilled H2O.

 

[Enkidu]

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

It is NOT a crucible, lol. We're looking at the same pic, right? It's a fritted filter funnel. I wouldn't use NaOH, because it'll eat away at the glass.

 

[nuke]

Yeah. It's a fritted Buchner/filter funnel. My bad. The NaOH will eat away the glass but it takes quite a while. You can use KOH if you're really paranoid.

 

[MurphyClox]

KOH in isopropanol works for almost all dirty glass ware. The corrosion of the glass' surface by the base is negligible and not important (exception: volumetric glassware loses it's accuracy).

I recommend a wash with acetone first.

- Murphy

 

[almost-]

Has 1-(4-Fluorophenyl)-2-methyl-2-aminopropane been tested in humans?

Seems to be readily available.

 

[nuke]

The mono-methylated version is readily available too and as phentermine sucks I can't see it being all that interesting.

 

[Artificial Emotion]

Please forgive my ignorance, but why would it be a bad idea to put my funnel in the dishwasher?!

Also, I selected my 'funnel' from a catalogue that stated quite clearly that it was a buchner funnel, so I can't understand how it can be wrong. It's the same catalogue used by most glassware suppliers in the UK.

 

[c0rt3x]

Has anyone out there tested this amazingly simple method:

From: DocMercury ® 15/03/2006 6:24:01 PM
Subject: QED @ COOH post id: 2146316
G'day all.


A simple queery of any chemists out there.

Simple methods for substitution with methyl group / removal of COOH from R?

From: Angus Prune ® 15/03/2006 6:26:43 PM
Subject: re: QED @ COOH post id: 2146323

To clarify, do you mean entirely removing the -COOH including the carbon atom, or keeping the carbon and making it -CH3?
From: Everyone Loves Iago ® 15/03/2006 6:28:21 PM
Subject: re: QED @ COOH post id: 2146328


React with lithium aluminium hydride in presence of ether to make a lithium salt of the acid,.. remove from ether, then in water will produce the primary alcohol. Then reduce the alcohol by any of various means.

From: DocMercury ® 15/03/2006 6:29:06 PM
Subject: re: QED @ COOH post id: 2146332

>>keeping the carbon and making it -CH3?

The usual mode a-la-decarboxylation.

From: hornedrhodent ® 15/03/2006 6:29:48 PM
Subject: re: QED @ COOH post id: 2146335
Making biodiesel Doc?
From: elfram ® 15/03/2006 6:31:17 PM
Subject: re: QED @ COOH post id: 2146341

If you mean removal of the -COOH group rather than reduction of the -COOH to -CH3, you need to search on decarboxylation of aliphatic carboxylic acids.

From: megsy ® 15/03/2006 6:32:33 PM
Subject: re: QED @ COOH post id: 2146346

I don't recommend playing with lithium aluminium hydride...super super reactive...

From: elfram ® 15/03/2006 6:33:20 PM
Subject: re: QED @ COOH post id: 2146350

I concur!

From: Everyone Loves Iago ® 15/03/2006 6:34:29 PM
Subject: re: QED @ COOH post id: 2146354

"I don't recommend playing with lithium aluminium hydride...super super reactive..."


Naturally I assume Doc is a trained organic chemist with the appropriate equipment and skills...

From: megsy ® 15/03/2006 6:36:03 PM
Subject: re: QED @ COOH post id: 2146359

Naturally I assume Doc is a trained organic chemist with the appropriate equipment and skills...

...

I made a rather large mess in the lab 'playing' with that stuff a few years ago...

From: DocMercury ® 15/03/2006 6:37:10 PM
Subject: re: QED @ COOH post id: 2146366

>>Making biodiesel Doc?

Nah, rocket fuel.

From: DocMercury ® 15/03/2006 6:44:01 PM
Subject: re: QED @ COOH post id: 2146396

Assume nothing!


From: DocMercury ® 15/03/2006 6:58:15 PM
Subject: re: QED @ COOH post id: 2146433

I wonder if sodium metal would serve the same purpose as LiAlH?

Or potassium metal? (got that)
From: the beervatar ® 15/03/2006 6:58:43 PM
Subject: re: QED @ COOH post id: 2146434

>>>Or potassium metal? (got that)


you booked your funeral?
From: DocMercury ® 15/03/2006 7:00:41 PM
Subject: re: QED @ COOH post id: 2146439

I also have some parrafin bottled Barium.

The Na was all used up making a bath for Mandy Vanstone. (cheap soap)
From: Angus Prune ® 15/03/2006 7:00:54 PM
Subject: re: QED @ COOH post id: 2146440

>>I wonder if sodium metal would serve the same purpose as LiAlH?<<

Doubtful.

>>Or potassium metal? (got that)<<

IT probably would not have the desired effect. But if you want to try, let the neighbours know so they can get a good vantage point when it blows up.

From: DocMercury ® 15/03/2006 7:04:12 PM
Subject: re: QED @ COOH post id: 2146454

Potassium is no worse than sodium (IME), and has a much prettier 'flame'....

From: PM 2Ring ® 15/03/2006 11:30:12 PM
Subject: re: QED @ COOH post id: 2147032

>Potassium is no worse than sodium (IME), and has a much prettier 'flame'....

Are you sure about that, Doc? I guess you must be, since you possess some K.... I've had plenty of 'hands-on' experience with Sodium metal, but I've never had the pleasure of meeting Potassium in person.

However, one of the old 'Open Learning' chem shows did a demo of the reaction of the lighter alkali metals with water. They showed Lithium, Sodium, Potassium and Rubidium. The Potassium reaction was definitely more vigorous than the Sodium reaction. Rubidium just explodes on contact with water. IIRC, Caesium & Francium explode on contact with the moisture in the air.

Also, one of my high-school science teachers had a few personal anecdotes about Potassium. I got the impression that K was much more dangerous than Na.

This teacher really knew his stuff. Not only was he a co-author of the science textbook, he'd worked as a chemist in industry for more than a decade before getting into teaching. His prac classes were the best. He told us that he liked to use large quantities of chemicals in his demos, so the class could see what was going on, and because he was used to putting a ton or so of stuff into an industrial processing line before stuff begins to come out the other end.

When he showed us Sodium reacting with tapwater, he used a huge Pyrex beaker and a whole chunk of Sodium. Impressive!


From: PM 2Ring ® 15/03/2006 11:33:21 PM
Subject: re: QED @ COOH post id: 2147040

>I don't recommend playing with lithium aluminium hydride...super super reactive...

>I made a rather large mess in the lab 'playing' with that stuff a few years ago...

Tell us the juicy details! I've been fascinated by LiAlH since I first heard about it, although I think I'd be scared to be in the same room with a reaction that used it.


From: PM 2Ring ® 15/03/2006 11:34:41 PM
Subject: re: QED @ COOH post id: 2147043

> Nah, rocket fuel.


What kind of rocket? Are you planning on going to outer space, or taking a trip to inner space?

From: PM 2Ring ® 15/03/2006 11:46:43 PM
Subject: re: QED @ COOH post id: 2147073

>React with lithium aluminium hydride in presence of ether

I wonder how easy they would be to obtain for the likes of Doc Mercury. If he's taken even a fraction of the drugs he alludes to, the guys at the chem supply houses will spot him the moment he walks through the door.

I know chemical suppliers tend to contact the authorities if they suspect that chemicals are being purchased for drug or explosive manufacture. So where do the speed labs, et al, get their solvents & catalysts these days? Do they bribe uni students & chem factory workers?

I wonder if there's an actual semi-organized black market in LiAlH, and similar reagents like BBr3? Or even solvents like ether & chloroform?

From: yempski ® 16/03/2006 7:20:26 PM
Subject: re: QED @ COOH post id: 2148711

I'm pretty sure you could also do the job using the Wittig reaction. I'd check, but my trusty copy of Morri and Boyd is more than 2Mm away

- yempski
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[c0rt3x]

Chemistry of Barbiturates

I'm wondering what was the structural most simple active barbiturate. Any suggestions?

 

[dread]

Barbital?

 

[ebola?]

Okay...what is 2-aminoindan's neuropharmacology like. I know that the empathogenic derivatives does present much dopaminergic action. . .

 

[almost-]

Yes, What is known about the SAR of barbiturates?

All I know is this what I read in an anesthesia article in my language.

It says that C5 must have aryl or alkyl chain of length 4-9 carbons for optimal activity, longer chains will cause seizures. Only one aryl group allowed in C5. Oxygen in C2 can be replaced with sulphur.

Alkyl groups in N1 and N3 potentiate anesthesia effects. If both N1 and N3 have substitution, compounds will cause seizures.

 

[c0rt3x]

Thank you, {almost-}, very much! ;-)

^^But what about that extremly interesting COOH --> CH3 issue?^^

If I consider Permastoned's avatar it seems to be quite obviously... :-D

If you don't like to discuss this in "the public" I'd really appreciate it if you PM me. ;-)

I've already tried simple electrolysis wich smelled like it was sucessfull - but my eyes and my brain told me the opposite... ;-)

 

[shibireru]

I realize that this probably doesn't belong even here, but I can't bring myself to make an appeal to BDDers. They don't have the wherewithal to even begin to provide sound advice, but that wouldn't stop them from responding with all kinds of asinine and obvious suggestions. It would be a complete waste of my time.

Okay. crosses fingers

In the past couple of weeks I have greatly increased the amounts and regularity of my consumption of diazepam and lorazepam in order to control my anxiety and I have already reached the point where, when the drugs are eliminated from my system, I experience severe rebound anxiety and insomnia - severe enough that I can not get a single minute of sleep. On the other hand, all the hypnotics that I can think of interfere with sleep architecture so that, while they do get one to sleep, they make one feel the next day as if he had gotten none at all. This seems to be especially true of the benzos I am taking.

So, I must use them and I must not, and I haven't gotten good sleep since I started taking them and my sleep debt is great enough at this point that I feel as if I were about to break and lose all contact with reality. It's getting worse and worse by the day and I'm becoming more and more mentally and emotionally unstable.

Is there a single fucking hypnotic that's commercially available that doesn't interfere with sleep architecture and allows one to get deep and restorative sleep? (I wish I had the knowledge and skills necessary to synthesize gaboxadol!)

I went to a number of doctors in my area and, surprise suprise!, none of them was able to offer any help. Ignorant gits.

The only things I've been able to come up with myself are cyproheptadine and trazodone and both of those look more than a little bit scary. Trazodone frequently causes akathisia and I seem to have a proclivity to experiencing that - severe forms of it too.

Please. I need some suggestions here.

/No diphenhydramine, alcohol, zaleplon, zolpidem, zopiclone, melatonin, ramelteon, tasimelteon, etc... All of it is shit