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Ketamine salts solubility

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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.
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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.
 
Hey i know this is old but just thought id add my 2 cents.

I can essentially confirm that making solutions with greater than 200mg/ml does not work well. Under 200mg/ml it dissolves completely and fairly quickly. With room temp water over 200mg/ml seems to be super saturated and the excess ketamine does not dissolve. Luckily, rarely will you find a user who needs more than 200mg for a hit! I only ever made solutions of this concentration (double the standard 1gram/10ml) so i could IM .5ml for 100mg, .75ml for 150mg, etc. Anyway i never took or needed a full 200mg dose!
 
KholdStare said:
Hey i know this is old but just thought id add my 2 cents.

I can essentially confirm that making solutions with greater than 200mg/ml does not work well. Under 200mg/ml it dissolves completely and fairly quickly. With room temp water over 200mg/ml seems to be super saturated and the excess ketamine does not dissolve. Luckily, rarely will you find a user who needs more than 200mg for a hit! I only ever made solutions of this concentration (double the standard 1gram/10ml) so i could IM .5ml for 100mg, .75ml for 150mg, etc. Anyway i never took or needed a full 200mg dose!
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I can second that, around the 200mg/ml mark for cold water is around the saturation point- has 250mg+/ml (I plug and have a tolerance- so sometimes I'll take 500-800mg in a k-hole 'session') has consistantly resulted in a load of undissolved powder that settled at the bottom which has dissolved with the addition of water (obviously I only liquify dry or 'street' ketamine, so it's definately not a cut that isn't dissolving as I've taken K this way all over the place, all over the world).

In addition, I can add that refridgerating (in a normal frigde on coldest setting), even over a long period, ketamine does not seem to effect solubility for me. However I know that all the ketamine I've ever taken has been racemic (the s-ket I took was PCP ;)), so prehaps coldness will cause precipitation/crystallisation.

Freezing liquid ketamine (once again, household freezer, lowest setting- don't know exact scientific temps) in water does not cause the ketamine to degrade, however it cause cause a very slight (just noticible) reduction in solubility- a little powder in a vial that will vanish instantly when shaken in the warmth of your hand.

Hot water seems to massively increase the solubility of ketamine. This is very important to note for IV users- if you use warm-hot water you can dissolve, 400mg/ml of ketamine. As the water cools, ketamine will precipitate out until it reaches room temp and around 200mg/ml. So PLEASE prep your ketamine shots using cold (sterile, from a break open vial & run your ket through a .2ug micronfilter) water and if you boil your water or something for IV then PLEASE let it return to room temp before you start mixing shit up, then leave it to cool for another 15 minutes in the barrel (unless you have scales, are familiar with your source, ymmv etc) just to make sure.

I've both heard the horror stories and seen the damage done by injecting ketamine solutions with the ketamine literally precipitating out of the water as it cooled in the barrel attached to the widegauge-needle injecting the solution + ketamine hci IM. Brutal shit.
 
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.
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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.
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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.
 
alkap555 said:
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.
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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.
 
Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum.

http://www.ncbi.nlm.nih.gov/pubmed/22191803

seems Mephedrone is not so neurotoxic as everyone thought.

While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels.
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Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands

Based on the structure of the superpotent 5-HT2A agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogs to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely-substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT2A over the 5-HT2C receptor, making it the most selective 5-HT2A receptor agonist ligand currently known.
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The latest in 5-HT2A agonists from Dave Nichols & Co.
 
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Torabora said:
Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum.

http://www.ncbi.nlm.nih.gov/pubmed/22191803

seems Mephedrone is not so neurotoxic as everyone thought.
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I'm really not that surprised. David Nutt pointed out that since Mephedrone became available cocaine related deaths in the UK plummeted while Mephedrone related deaths are comparatively nonexistent, so at least in his opinion Mephedrone is far less toxic than cocaine overall.
 
Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux.

http://www.ncbi.nlm.nih.gov/pubmed/22722938

Free Full Text!
Some great reading about the intracellular mechanisms that mediate amphetamine's DAT reversal, it also suggests that there is a far more complex interplay within the cell resulting in the cascade leading to PKC-Beta's phosphorylation of Thr53.

Must resist urge to look up known modulators of DAT and interactions of mentioned proteins... Must study for MCAT...
 
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