• N&PD Moderators: Skorpio | thegreenhand

⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

Clinical toxicology of newer recreational drugs:

http://www.filesonic.com/file/2857293425

From the MXE article:





Can you really call it illicit use if it's not illegal?

^ They do say, "mechanism of action likely involves... formal pharmacology has not yet been determined." And it sounds more like he just freaked out and called an ambulance rather than really overdosed, heart rate and blood pressure weren't that high.

More than likely to be honest. Since the guy hasnt used before so he probably count even imagine how deep MXE can be

Does MXE cause fever? ive noticed that before on normal dosages
 
Incidentally, why use filesonic - have to wait to download, enter a captcha... I don't understand why everyone doesn't use sendspace, so much less hassle. %)

I didn't realise sorry, I've got an account. I'll try that instead next time.
 
Does MXE cause fever? ive noticed that before on normal dosages

borohydride, the former opiophile forums 'chemist extraordinaire' said it was actually a powerful opioid prodrug in the following post from there:

Methoxetamine is an opioid prodrug. If the methoxy is deprotected (a small bit is in the body) then 10-20mg will wipe out anyone - even someone with a habit. If the =O is para then 1-2mg does it!!!


BTW if the structure doesn't remind you of an opioid then look at the work of Daniel Lednicer:



4-Amino-4-arylcyclohexanones and Their Derivatives, a Novel Class of Analgesics. 1. Modification of the Aryl Ring
Daniel Lednicer, Philip F. VonVoigtlander and D. Edward Emmert

The Upjohn Company, Research Laboratories, Kalamazoo, Michigan 49001. Received August 7, 1979

J. Med. Chem 1980, 23, p424-430

Perhaps precipitated withdrawal?
 
Methoxetamine is an opioid prodrug. If the methoxy is deprotected (a small bit is in the body) then 10-20mg will wipe out anyone - even someone with a habit. If the =O is para then 1-2mg does it!!!

At risk of further derailment - Sorry to be skeptical, but is there any evidence other than the claims of some alleged "chemist extraordinaire"? :\
 
anyone have a link for the full text here [...] Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

You can download the article here.
Moderators if this isn't allowed I didn't know. Remove link if necessary.
 
Visualization of the Cocaine-Sensitive Dopamine Transporter with Ligand-Conjugated Quantum Dots

It appears we are getting ever closer to mapping DAT.

At risk of further derailment - Sorry to be skeptical, but is there any evidence other than the claims of some alleged "chemist extraordinaire"? :\

Not from me, but I thought it worth mentioning.

EDIT; actually:

3-MeO-PCP and 3-MeO-PCE are simply incredible drugs. They have a true capacity for healing, as the 3-methoxy group infers µ-opioid receptor affinity³ and removes the manic pressure of thought that can make PCP quite a disturbing and unpleasant drug.

Interview with a Ketamine Chemist (Or to Be More Precise, an Arylcyclohexylamine Chemist) By Hamilton Morris

From the mouth of the *inventor* of Methoxetamine.
 
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Well, to be fair, SERT knockout produced the expected results.. but how to explain the catecholamine release? VMAT2?

And if MDMA/MDA doesn't bind to SERT in humans, what stimulates 5HT release?

Lots of questions now about MDMA's mechanism of action, I guess.

Correct me if I'm wrong, but hasn't 5HT1A receptor agonism been shown to induce dopamine release?

Edit: Perhaps MDMA's 5-HT2B receptor agonism contributes to its dopamine/serotonin release?
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007952
 
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Dick.
Just kidding. I should have taken my own advice and run a search. :p

ebola
 
Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs.
Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, Mackerell AD Jr, Brezina V, Sealfon SC, Filizola M, González-Maeso J, Logothetis DE.
Cell 2011.

Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

http://www.ncbi.nlm.nih.gov/pubmed/22118459
 
Oh man, our bodies are complex systems that can't be characterised by the actions of individual receptors in vacuo? Say it ain't so!

That paper made me warm and fuzzy inside.
 
It's been way too long since anyone posted in this thread, so let's get this going again! I'll start:

Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'.
Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A.
School of Anthropology, University of Arizona, Tucson, AZ 85721, USA. [email protected]
J Exp Biol. 2012

Abstract
Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors.


Pubmed link:
http://www.ncbi.nlm.nih.gov/pubmed?...als with implications for the ʻrunnerʼs highʼ

Free (I think) full text:
http://www.ic.arizona.edu/~raichlen/DavePDF/RaichlenEtAl2012.pdf


I'm not sure how much you can take from their comparison to ferrets, but the correlation between circulating anandamide and their measures of "runner's high" is pretty solid. Now I'd like to see them repeat this with half of their participants on Rimonabant to show that the effect goes away, but it's a good start anyways.

The most interesting thing to me was their outlier in figure 2. Holy cow, this guy got a 19x increase in anandamide and a 17x increase in positive affect! Who doesn't want to be that guy, 30 minute run = bong hit.
 
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Here is an interesting paper from Nature Neuro regarding the strx elucidation of the GABAb receptor, which is IMO has largely been ignored as a pharmacological target (except for the obvious baclofen, GHB agonists). To my knowledge this is the first paper that characterizes the strx, fxn, and interaction of different subunits of the GABAb receptor.

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABAB receptor is a G protein–coupled receptor central to mammalian brain function. Malfunction of GABAB receptor has been implicated in several neurological disorders. GABAB receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimeric interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABAB receptor that is unique to the GABAergic system.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3133.html

The paper is pretty comprehensive, including X-ray strx elucidation, electrophys, and some ligand binding-conformational change assays. They highlight the strxural and fxnal differences between the GABAbR and related GPCRs such as the mGluRs. Very cool.
 
Here is an interesting paper from Nature Neuro regarding the strx elucidation of the GABAb receptor, which is IMO has largely been ignored as a pharmacological target (except for the obvious baclofen, GHB agonists). To my knowledge this is the first paper that characterizes the strx, fxn, and interaction of different subunits of the GABAb receptor.



http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3133.html

The paper is pretty comprehensive, including X-ray strx elucidation, electrophys, and some ligand binding-conformational change assays. They highlight the strxural and fxnal differences between the GABAbR and related GPCRs such as the mGluRs. Very cool.

Wonder if this will lead to any interesting SAR predictions on the RC market? Let's hope it a
stays with big pharma.
 
Agreed. I think this whole RC craze is getting out of control. Sooner or later someone is bound to knock up a batch of really toxic shit and potentially hurt a whole lotta people.
 
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