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Ketamine salts solubility

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Well I'll be damned. The rumors are true. Or at least, they appear to be.

The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties
Neuropsychopharmacology (2013) 38, 2373–2384; doi:10.1038/npp.2013.135; published online 3 July 2013

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz’s behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz’s prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.
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Is there anything else with a similar SAR? Lorcaserin came to mind but I just checked and it's very different. RH-34 was my second thought but that's also quite dissimilar.

150px-Efavirenz_skeletal.svg.png

Efavirenz
200px-Lorcaserin.svg.png

Lorcaserin
220px-RH-34_structure.png

RH-34
 
Reverend Random said:
Apparently, NMDA-agonists also show anti-depressant properties, similar to ketamine's NMDA antagonism. News article here, abstract here.
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It sounds like they're using a glycine transporter inhibitor rather than a direct NMDA agonist. I think a direct NMDA agonist would be fairly neurotoxic. Very exciting never the less.

Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression
Background
Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.

Methods
We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.

Results
Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.

Conclusions
Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.
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Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists

http://pubs.acs.org/doi/abs/10.1021/cn400216u

<quote>N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor</quote>
 
This article appears to be hot shit. When in search of selectivity for 5ht2a over 5ht2c and compounds that act more as partial agonists, it looks like there are some quite overlooked moieties. Let me give more elaborate commentary when I'm less high. ;)

ebola
 
Okay, so it looks like the cyano substitution at the 4 confers high selectivity for 5ht2a. And it looks like methylenedioxybenzyl (and to some extent, fluorobenzyl) confers partial agonism. So we know where to turn for increased safety. The nboh series seems super-similar to the prior nbomes, so the recent emergency scheduling essentially accomplished nothing.

PRL-8-53
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What an interesting compound. It looks like cholinergic enhancement is its most likely mechanism. I bet it would make for a good adjunct to stimulant use (ideally with reduced stimulant dosages).

ebola
 
Based upon back-of-the-napkin calculations, the NBOH's seem like overall "better" drugs from a pharmacokinetic point of view; the little bit of extra polarity from the OH means they will be eliminated a little faster.
 
mmm...I'm not sure whether this is good or bad, as the nbomes are hardly 'long-burners' already, and redosing with these compounds works particularly poorly. Sometimes, you just want something more enduring than, say, metocin, for example. Also, wouldn't we expect clearance to be mainly hepatic (via the same enzymes that metabolize benzphetamine)? Would increased polarity mainly increase the rate of clearance by the kidneys?

ebola
 
i see it was already shared on this page, but its worth resharing. and embedded this time instead of linked.

ld50.png
 
We are quite the social bunch aren't we?
How's the new year been so far for every bodies continued education in the subject? I've been slacking and falling back into my week long binges on wars and cultures of antiquity instead of science... Read a lot if the 16 Great Turkic Empires this week.
 
For the last decade, I've been a social scientist with specialization in classical and contemporary sociological theory (with intermittent work in statistical analysis and some research work in cognitive neuroscience from long ago). It seems that I've somehow just osmosed a lot of information? :p

ebola
 
ebola? said:
mmm...I'm not sure whether this is good or bad, as the nbomes are hardly 'long-burners' already, and redosing with these compounds works particularly poorly. Sometimes, you just want something more enduring than, say, metocin, for example. Also, wouldn't we expect clearance to be mainly hepatic (via the same enzymes that metabolize benzphetamine)? Would increased polarity mainly increase the rate of clearance by the kidneys?

ebola
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Speaking of clearance. There is another paper out by the same group about metabolism of NBOMes

Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability

2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet very little is known about the relationships between the structure of the ligands and their pharmacokinetic profile. In order to evaluate the potential of these compounds for in vivo applications we have determined the microsomal stability of 11 phenethylamines and 27 N-benzylated derivatives thereof using human liver microsomes. We found that the N-benzylated phenethylamines have much higher intrinsic clearance than the parent phenethylamines. We hypothesize that their low hepatic stability renders them orally inactive due to first pass metabolism, which is supported by anecdotal data from recreational use of these compounds.

http://dx.doi.org/10.1007/s11064-014-1253-y
 
The title of this thread made me quite literally laugh out loud. Am I easily amused?

Passing a slow evening by reading everything and anything that I can find on allylescaline. It's a strange little side-interest of mine, the mescaline family.
 
I recognized it. I adore xkcd. I remember seeing that comic when it was published and being pleasantly surprised by the reference.
 
J Clin Psychopharmacol. 2014 Feb 12. [Epub ahead of print]
Methylphenidate Enhances Cognitive Performance in Adults With Poor Baseline Capacities Regardless of Attention-Deficit/Hyperactivity Disorder Diagnosis.
Agay N, Yechiam E, Carmel Z, Levkovitz Y.
We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.
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More evidence that, maybe, stimulants are just good at making people task-oriented, rather than are a "treatment" for anything? I never really bought into the whole "stimulants effect people with AD(H)D differently"... given that, y'know, people in general experience drugs differently, and set and setting need to be considered. Also, given that stimulants like methylphenidate, amphetamine and the like precede the ADHD explosion, and have been known to enhance cognitive performance (in some contexts) for a long damn time.
 
Front. Integr. Neurosci., 26 February 2014 | doi: 10.3389/fnint.2014.00020
The claustrum’s proposed role in consciousness is supported by the effect and target localization of Salvia divinorum
Klaus M. Stiefel, Alistair Merrifield and Alex O. Holcombe

This article brings together three findings and ideas relevant for the understanding of human consciousness: (I) Crick’s and Koch’s theory that the claustrum is a “conductor of consciousness” crucial for subjective conscious experience. (II) Subjective reports of the consciousness-altering effects the plant Salvia divinorum, whose primary active ingredient is salvinorin A, a κ-opioid receptor agonist. (III) The high density of κ-opioid receptors in the claustrum. Fact III suggests that the consciousness-altering effects of S. divinorum/salvinorin A (II) are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the cortex, mainly in prefrontal areas. Consistent with Crick and Koch’s theory that the claustrum plays a key role in consciousness (I), the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen lysergic acid diethylamide (LSD). Based on this data and on the relevant literature, we suggest that the claustrum does indeed serve as a conductor for certain aspects of higher-order integration of brain activity, while integration of auditory and visual signals relies more on coordination by other areas including parietal cortex and the pulvinar.
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