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Nagelfar

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^one time a voice told me where to find a old cellphone I had lost days previous in the bushes off a hill in a park by saying "hot" or "cold" and responded with "you're welcome" after I found it. No one was around. Leverich park in Vancouver WA. I was tweaking, take that subconsciously into account.
 

S.J.B.

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wonder what the mechanism is for this
Looking at the original patent, it's at 175 C under hydrogen over nickel, so my guess is it's just hydrogenolysis of the C-O bond followed by dialkylation of ammonia.
 

sekio

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The odor of street cocaine and the compound that dogs will respond to is not cocaine itself, but rather methyl benzoate formed by transesterifcation.

There is actually a patent: US4260517A - Available aroma of cocaine.

When methyl benzoate is volatilized and then highly diluted with a gaseous non-odor masking diluent, the aroma of cocaine is provided. Similarly, when a mixture of methyl benzoate, methyl cinnamate and the dimethyl ester of truxillic acid is volatilized and then highly diluted with a gaseous non-odor masking diluent, the aroma of various grades of "street cocaine" is provided.

A unique feature of the present invention is that the aroma of cocaine is not merely imitated, but rather, the actual aroma of cocaine is provided without the use of any cocaine or cocaine related materials. Since the actual aroma of cocaine is provided by the present invention, it is possible to use the present invention to establish a chemical model for the aroma of cocaine. This chemical model may then be used in various qualitative and quantitative analytical techniques.


Now you can formulate a perfume that smells like Peruvian flake. And, as a bonus, you can make life hard for anyone who passes by a drug-sniffing dog (maybe useful as a diverting tactic).

I find it interesting that Sigma apparently sells a synthetic cocaine odorant to train police dogs on. My money's on it being the above composition.

Bonus questions for the curious (my answers below):
1. Why does high quality cocaine contain mostly methyl benzoate?
2. How does truxillic acid form?
NSFW:
1. The oxidation with permanganate would destroy the truxillic acids & cinnamic acids
2. Photochemical dimerization! Two molecules of cinnamic acid will couple together.
 
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sekio

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journal dump


Bis(4-hydroxy-N-isopropyl-N-methyltryptammonium) fumarate: a new crystalline form of miprocin
Andrew R. Chadeayne,a* Duyen N. K. Pham,b James A. Golenb and David R. Mankeb
The title compound, bis(4-hydroxy-N-isopropyl-N-methyltryptammonium) (4-HO-MiPT) fumarate (systematic name: bis{[2-(4-hydroxy-1H-indol-3-yl)ethyl](methyl)propan-2-ylazanium} but-2-enedioate), 2C14H21N2O+·C4H2O42−, has a singly protonated tryptammonium cation and one half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by N—H⋯O and O—H⋯O hydrogen bonds. [...]

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels
Marika Heblinski, Marina Santiago, Charlotte Fletcher, Jordyn Stuart, Mark Connor, Iain S. McGregor, and Jonathon C. Arnold
Published Online:9 Mar 2020

Results: α-pinene, β-pinene, β-caryophyllene, linalool, limonene, β-myrcene or α-humulene did not affect [Ca]i in hTRPA1 and hTRPV1 overexpressing cells. Cinnamaldehyde (CA), Δ9-THC, and 2-arachidonoylglycerol (2-AG) activated TRPA1 receptors with high efficacy and similar potency (EC50s of ∼10 μM). Capsaicin and anandamide (AEA) activated TRPV1 receptors with an EC50 of 61 nM and 4.3 μM, respectively, but TRPV1 showed no response to Δ9-THC, cannabidiol, and other minor cannabinoids. Terpenoids did not significantly affect the responses of TRPA1 and TRPV1 receptors to submaximal and maximal concentrations of CA and Δ9-THC or the endocannabinoids AEA and 2-AG.

Discussion: We could not find any evidence that the terpenoids tested here activate TRPA1 and TRPV1 channels or modulate their activation by Δ9-THC and other agonists, including endocannabinoids.

Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate
Dan Wu and View ORCID ProfileDonal F. O’Shea
PNAS March 24, 2020 117 (12) 6349-6355; first published March 10, 2020

Abstract

A combined analytical, theoretical, and experimental study has shown that the vaping of vitamin E acetate has the potential to produce exceptionally toxic ketene gas, which may be a contributing factor to the upsurge in pulmonary injuries associated with using e-cigarette/vaping products. Additionally, the pyrolysis of vitamin E acetate also produces carcinogen alkenes and benzene for which the negative long-term medical effects are well recognized. As temperatures reached in vaping devices can be equivalent to a laboratory pyrolysis apparatus, the potential for unexpected chemistries to take place on individual components within a vape mixture is high. Educational programs to inform of the danger are now required, as public perception has grown that vaping is not harmful.

Br J Anaesth. 2018 Jul;121(1):260-269. doi: 10.1016/j.bja.2018.03.014. Epub 2018 May 10.
Dreaming and awareness during dexmedetomidine- and propofol-induced unresponsiveness.
Radek L1, Kallionpää RE2, Karvonen M3, Scheinin A4, Maksimow A5, Långsjö J6, Kaisti K7, Vahlberg T8, Revonsuo A9, Scheinin H10, Valli K11.
BACKGROUND:

Experiences during anaesthetic-induced unresponsiveness have previously been investigated by interviews after recovery. To explore whether experiences occur during drug administration, we interviewed participants during target-controlled infusion (TCI) of dexmedetomidine or propofol and after recovery.
METHODS:

Healthy participants received dexmedetomidine (n=23) or propofol (n=24) in stepwise increments until loss of responsiveness (LOR1). During TCI we attempted to arouse them for interview (return of responsiveness, ROR1). After the interview, if unresponsiveness ensued with the same dose (LOR2), the procedure was repeated (ROR2). Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness (LOC), infusion terminated, and the participants interviewed upon recovery (ROR3). An emotional sound stimulus was presented during LORs and LOC, and memory for stimuli was assessed with recognition task after recovery. Interview transcripts were content analysed.
RESULTS:

Of participants receiving dexmedetomidine, 18/23 were arousable from LOR1 and LOR2. Of participants receiving propofol, 10/24 were arousable from LOR1 and two of four were arousable from LOR2. Of 93 interviews performed, 84% included experiences from periods of unresponsiveness (dexmedetomidine 90%, propofol 74%). Internally generated experiences (dreaming) were present in 86% of reports from unresponsive periods, while externally generated experiences (awareness) were rare and linked to brief arousals. No within drug differences in the prevalence or content of experiences during infusion vs after recovery were observed, but participants receiving dexmedetomidine reported dreaming and awareness more often. Participants receiving dexmedetomidine recognised the emotional sounds better than participants receiving propofol (42% vs 15%), but none reported references to sounds spontaneously.
CONCLUSION:

Anaesthetic-induced unresponsiveness does not induce unconsciousness or necessarily even disconnectedness.
 

polymath

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Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate
Dan Wu and View ORCID ProfileDonal F. O’Shea
PNAS March 24, 2020 117 (12) 6349-6355; first published March 10, 2020

Abstract

A combined analytical, theoretical, and experimental study has shown that the vaping of vitamin E acetate has the potential to produce exceptionally toxic ketene gas, which may be a contributing factor to the upsurge in pulmonary injuries associated with using e-cigarette/vaping products. Additionally, the pyrolysis of vitamin E acetate also produces carcinogen alkenes and benzene for which the negative long-term medical effects are well recognized. As temperatures reached in vaping devices can be equivalent to a laboratory pyrolysis apparatus, the potential for unexpected chemistries to take place on individual components within a vape mixture is high. Educational programs to inform of the danger are now required, as public perception has grown that vaping is not harmful.
Looks like this chemical is about as toxic as fluorine gas according to some estimates.

 
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sekio

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Ketene gas is not only super toxic, about as toxic as phosgene, but it's also very reactive and flammable. One old school means of preparing acetic anhydride was by means of a 'ketene lamp' - a sealed glass apparatus where acetone vapor is drawn over a hot nichrome wire, pyrolysing it to methane and ketene, the latter of which reacts with glacial acetic acid to form acetic anhydride. A lab-scale generator can do 40 grams of acetic anhydride an hour, I'm told.

NSFW:


If you ask me, it's a death trap. The obvious hazard presented by bringing flammable vapors in contact with extreme heat, means rigorous exclusion of the atmosphere and any oxygen is a must. A good thick blast shield wouldn't be too much PPE.

I'm amazed that anyone managed to do this process and survive. For whatever reason, it was deemed reliable enough to be included in Vogel. There is even a related synthesis in OrgSyn using acetone vapor passed through a packed tube heated over open flame....

In chemistry news,
First steps towards a stable neon compound: observation and bonding analysis of [B12(CN)11Ne]−
Abstract

Noble gas (Ng) containing molecular anions are much scarcer than Ng containing cations. No neon containing anion has been reported so far. Here, the experimental observation of the molecular anion [B12(CN)11Ne]− and a theoretical analysis of the boron–neon bond is reported.


Talk about an unfavorable bond. I'm suprised.
 

sekio

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Metab Eng. 2020 Mar 26. pii: S1096-7176(19)30401-X. doi: 10.1016/j.ymben.2019.12.007. [Epub ahead of print]
Metabolic engineering of Saccharomyces cerevisiae for the production of psilocybin and related tryptamine derivatives.
Milne N, Thomsen P, Knudsen NM, Rubaszka P, Kristensen M, Borodina I.

Psilocybin is a tryptamine-derived psychoactive alkaloid found mainly in the fungal genus Psilocybe, among others, and is the active ingredient in so-called "magic mushrooms". Although its notoriety originates from its psychotropic properties and popular use as a recreational drug, clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. In this work, we demonstrate the de novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae by expression of a heterologous biosynthesis pathway sourced from Psilocybe cubensis. Additionally, we achieve improved product titers by supplementing the pathway with a novel cytochrome P450 reductase from P. cubensis. Further rational engineering resulted in a final production strain producing 627 ± 140 mg/L of psilocybin and 580 ± 276 mg/L of the dephosphorylated degradation product psilocin in triplicate controlled fed-batch fermentations in minimal synthetic media. Pathway intermediates baeocystin, nor norbaeocystin as well the dephosphorylated baeocystin degradation product norpsilocin were also detected in strains engineered for psilocybin production. We also demonstrate the biosynthetic production of natural tryptamine derivative aeruginascin as well as the production of a new-to-nature tryptamine derivative N-acetyl-4-hydroxytryptamine. These results lay the foundation for the biotechnological production of psilocybin in a controlled environment for pharmaceutical applications, and provide a starting point for the biosynthetic production of other tryptamine derivatives of therapeutic relevance.


Hell yeah. 1200 mg of alkaloids per liter means a 1 liter reactor could produce almost 250 5 milligram doses, or the equivalent of a gram of shrooms for every 8 mL of broth.

Move over, mushrooms!
 

sekio

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Dopamine promotes cognitive effort by biasing the benefits versus costs of cognitive work
A. Westbrook, R. van den Bosch, J. I. Määttä, L. Hofmans, D. Papadopetraki, R. Cools, M. J. Frank
Science 20 Mar 2020: Vol. 367, Issue 6484, pp. 1362-1366 DOI: 10.1126/science.aaz5891
Psychostimulants have a place in the therapy of attentional disorders. However, they are also widely used off-label to enhance cognitive performance, and their mechanisms of action remain elusive. Westbrook et al. studied the effects of these drugs and concurrently measured striatal dopamine synthesis capacity in young, healthy participants (see the Perspective by Janes). They administered a placebo, methylphenidate (a dopamine and noradrenaline reuptake blocker), and sulpiride (a selective D2 receptor antagonist) while participants made explicit cost-benefit decisions about whether to engage in cognitive effort. Higher dopamine synthesis capacity in the caudate nucleus was associated with greater willingness to allocate cognitive effort. In addition, methylphenidate and sulpiride increased subjective values and motivation to work specifically for people with low dopamine synthesis capacity. Cognition-enhancing drugs may thus act at the motivational level rather than directly boosting cognition per se.
 

sekio

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Selective Extraction of Cannabinoid Compounds from Cannabis Seed Using Pressurized Hot Water Extraction
by Yannick Nuapia, Hlanganani Tutu, Luke Chimuka and Ewa Cukrowska
Molecules 2020, 25(6), 1335; https://doi.org/10.3390/molecules25061335
Phytochemicals of Cannabis sativa mainly for the use in the different industries are that of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Pressurized hot water extraction (PHWE) is seen as an efficient, fast, green extraction technique for the removal of polar and semi-polar compounds from plant materials. The PHWE technique was applied to extract cannabinoid compounds from Cannabis sativa seed. Response surface methodology was used to investigate the influence of extraction time (5–60 min), extraction temperature (50–200 °C) and collector vessel temperature (25–200 °C) on the recovery of delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBG) and cannabigerol (CBC) from Cannabis sativa seed by PHWE. The identification and semi quantification of cannabinoid compounds were determined using GCXGC-TOFMS. The results obtained from different extractions show that the amount of THC and CBN was drastically decreasing in the liquid extract when the temperature rose from 140 to 160 °C in the extraction cell and the collector′s vessel. The optimal conditions to extract more CBD, CBC, and CBG than THC and CBN were set at 150 °C, 160 °C and 45 min as extraction temperature, the temperature at collector vessel, and the extraction time, respectively. At this condition, the predicted and experimental ratio of THCt (THC + CBN)/CBDt (CBD + CBC+ CBG) was found to be 0.17 and 0.18, respectively. Therefore, PHWE can be seen as an alternative to the classic extraction approach as the efficiency is higher and it is environmentally friendly.

I had no idea you could extract cannabinoids from seeds? And with hot water as a solvent, too? Can you extract hash oil from buds with supercritical steam?
 

sekio

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Structure–Activity Relationship Study of Psychostimulant Synthetic Cathinones Reveals Nanomolar Antagonist Potency of α-Pyrrolidinohexiophenone at Human Muscarinic M2 Receptors
Yiming Chen, Clinton E. Canal*
ACS Chem. Neurosci. 2020, 11, 6, 960-968 Publication Date:February 19, 2020 https://doi.org/10.1021/acschemneuro.0c00008
Synthetic cathinones (SCs) are designer, psychostimulant drugs of abuse that primarily act on monoamine transporters; little is known about their off-target liability. Abuse of pyrrolidine-containing SCs, such as α-PHP, has been linked to clinical features, including tachycardia and hypertension, and psychiatric events, including delusions and memory impairments—effects mimicking deliriant hallucinogens that are acetylcholine muscarinic receptor (MR) antagonists. α-PHP and nine analogs with modifications in the α-carbon side chain length and/or containing a methylenedioxy moiety were screened for activity at each of the five human MRs. Increasing the length of the α-carbon side chain of 1-phenyl-2-(pyrrolidin-1-yl)ethan-1-one analogs from a methyl (α-PPP) to a propyl (α-PVP) group caused a steep increase in affinity at all MR subtypes, and one extra carbon (α-PHP) further enhanced MR affinity; the presence of a methylenedioxy moiety generally hindered this effect. Highest MR affinity was observed with α-PHP at M2Rs—its M2R affinity (Ki = 251 nM) was 302-fold higher than α-PPP’s. M2R–cAMP inhibition and β-arrestin recruitment assays showed that α-PHP is an M2R antagonist (Kb = 120 and 502 nM, respectively). Additional experiments showed α-PHP is also an antagonist of M1R–inositol phosphate production (Kb = 1.4 μM). Human toxicology studies report blood concentrations of pyrrolidine-containing SCs, including α-PHP, that reach micromolar levels during intoxication, indicating α-PHP’s MR activity might have physiological relevance. As M2Rs and M1Rs are widely expressed in the autonomic and central nervous systems, α-PHP’s anticholinergic activity might be relevant to adverse events associated with α-PHP intoxication.
 

sekio

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Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids
Samuel Obeng, Shyam H. Kamble, Morgan E. Reeves, Luis F. Restrepo, Avi Patel, Mira Behnke, Nelson J.-Y. Chear, Surash Ramanathan, Abhisheak Sharma, Francisco León, Takato Hiranita, Bonnie A. Avery, Lance R. McMahon, Christopher R. McCurdy
Cite this: J. Med. Chem. 2020, 63, 1, 433-439 Publication Date:December 13, 2019 https://doi.org/10.1021/acs.jmedchem.9b01465

Gives Ki values at opioid receptors and adrenergic receptors for several major Kratom alkaloids. The summary:
Corynantheidine half life 6min, Ki 118 nM at mu, 1910 nM at kappa, 41 nM at alpha-1D.
9-Hydroxycorynantheidine, half life 180 min, Ki 105 nM at mu.
Mitragynine half life 20 min, Ki 161 nM at mu, 198 nM at kappa, 1300-9600 nM at the various adrenergic receptors. (1A > 2C > 1B = 2A > 1B > 2B)
7-Hydroxymitragynine half life 170 min, Ki 7 nM at mu, 74 nM at kappa, 236 nM at delta.
Speciociliatine half life 42 min, Ki 54.5 nM at mu, 116 nM at kappa.

Further studies con-ducted to investigate the in vivo functional effects of mitragynine, 7-hydroxymitragynine, and speciociliatine using the hotplate test at 52 ± 0.1 ̊C revealed that 7-hydroxymitragynine and speciociliatine produced maximum response (100 % MPE) with 7-hydroxymitragynine being more potent than speciociliatine and morphine but less potent than fentanyl. Speciociliatine had a similar potency to morphine and mitragynine had the least efficacy among the compounds testedat the highest dose assayed. The antinociceptive effect of 7-hydroxymitragynine was reversed by 0.1 mg/kg naltrexone which suggest that 7-hydroxymitragynine may be acting through the MOP as demonstrated by the binding and in vitro functional as-says. Speciociliatine had antinociceptive effects at 10mg/kg; however, this dose produced lethality in 5/21 rats tested, indicating a narrow therapeutic window. Since the ED50 of speciociliatine to produce antinociception is close to its LD50 value, in this acute antinociception assay (i.e., hotplate test) it was not feasible to evaluate the extent to which the antinociception observed was due to activation of opioid receptors by conducting antagonism tests with opioid sub-type antagonists. In addition, speciociliatine similar to U69593 produced hypothermia but not 7-hydroxymitragynineormitragynine. Collectively, this profile of in vivo activity may indicate that speciociliatine is acting, at least in part, through non-opioids receptors.
 

S.J.B.

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Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors
Corresponding author: Richard A. Glennon (Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, United States)
ACS Chemical Neuroscience 2020, Volume 10, Issue 9, Pages 4043-4050
Published online August 1st, 2019
https://doi.org/10.1021/acschemneuro.9b00284
Synthetic cathinones are, primarily, stimulant drugs of abuse that act at monoamine transporters (e.g., the dopamine transporter or DAT) as releasing agents or as reuptake inhibitors. In the past few years, the emergence of >150 new synthetic cathinones has attracted considerable attention from medical and law enforcement communities. threo-Methylphenidate (tMP), used clinically for the treatment of ADHD and narcolepsy, is also a DAT reuptake inhibitor. tMP is somewhat structurally similar to abused cathinone stimulants, and the structure–activity relationships (SAR) of tMP have been well-defined. Hence, available tMP literature might assist in understanding the SAR of synthetic cathinones, about which less is known. In the present study, we synthesized and examined eight 2-benzoylpiperidine analogues (4, 612) to determine if tMP SAR might be applicable to cathinone SAR. The benzoylpiperidine analogues were evaluated in a competition assay using live-cell imaging against APP+ in HEK293 cells stably expressing hDAT and in cells coexpressing DAT and voltage-gated Ca2+ channels. All compounds were found to be DAT reuptake inhibitors, and a significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91), suggesting that the SAR of tMP analogues might be directly applicable to certain synthetic cathinones as DAT reuptake inhibitors.
It seems that the cathinone analogues of methylphenidate are significantly less potent DRIs, but the ring-subsitution SAR tracks well:



The only cathinone of the series found to be more potent than methylphenidate was 2-(3,4-dichlorobenzoyl)piperidine:



Interestingly, 2-benzylpiperidine was only about 4 times less potent than the corresponding cathinone. If the ring-substitution trend holds for the benzylpiperidines as well, could 2-(3,4-dichlorobenzyl)piperidine be an active DRI at a reasonable dosage?

 
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