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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, 6–12) 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.
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It seems that the cathinone analogues of methylphenidate are significantly less potent DRIs, but the ring-subsitution SAR tracks well:

methylphenidate_analogues_cathinones_sar.jpeg


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

2-(3%2C4-dichlorobenzoyl)piperidine.png


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?

2-(3%2C4-dichlorobenzyl)piperidine.png
 
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shame they did not test the alcohols/esters too (phacetoperane etc)
220px-Phacetoperane_chemical_structure.png
 
Steve Urkelamine, the nerdiest dopamine agonist on the block.

 
The Combat Methamphetamine Epidemic Act of 2005 [...]

is it just me or do I read this as an epidemic of "combat methamphetamine" (c.f "assault weapon") ? like what, are people abusing the SECRET MILITARY CRANK all over America?
 
Yep. The US and UK preferred benzedrine (amphetamine) but the Germans used methamphetamine.

I also note that MDMA has an INN now: Midomafetamine. Ask your doctor today.
 
I can already see the TV ads for it haha.

"Are you sick and tired of not feeling love and connection with those you care about? Ask your doctor about midomafetamine, the only drug proven to help you feel love for everyone! Even that total stranger over there!"
 
clubcard said:
Now CHARMM was written in 'modern' Fortran 96, a programming language which I know not a single thing. Has anyone had the thrill-seeking job of rewriting Fortran 96 into Java?
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There are some programs, findable with Google search, that translate Fortran code to C++ or Java, but I find it hard to believe that they always always produce a functioning result without you doing some corrections by hand afterwards. I think Fortran makes it a bit easier to use parallel processing in scientific computation than C++. At least that was the impression I got when listening to a Fortran parallel computing lecture some years ago.
 
Radiation‐induced Changes in Stimulant Pharmacokinetics Relevant to Long‐distance Space Travel
Michael D. Hambuchen, Anna Mazur, David L. Findley, Mitchell R. McGill
First published: 17 April 2020
A round trip to Mars or a 10 year stay on the planet’s surface is estimated to be associated with 1 or 3 Gray (Gy) whole body radiation exposure, respectively. Radiation exposure is known to alter the pharmacokinetics of some medications. The objective of these experiments was to determine how radiation exposure may alter drug pharmacokinetics in male Wistar rats using methamphetamine (METH) as a probe. METH was chosen due to its well established pharmacokinetics in rats and the relevance of stimulant administration for alertness in space travel. Rats were exposed to 0, 1, or 3 Gy X‐ray radiation followed by measurement of clearance‐related serum biomarkers (e.g., alanine aminotransferase, serum creatinine, etc.), 1 mg/kg subcutaneous (SC) METH pharmacokinetics, and 1 mg/kg SC METH‐induced locomotor activity (which is correlated with brain METH concentrations). While radiation dose‐dependently reduced rat total body weight and spleen weight, there were no significant changes in serum biomarkers, METH pharmacokinetic parameters, or METH‐induced locomotor activity. In conclusion, acute Mars travel relevant radiation exposures did not alter METH disposition, but longer‐term studies of gradual radiation exposure on stimulant pharmacokinetics are needed.

x-rays and meth whooo what a party
 
LSD in pubic hair in a fatality
Jean-michel Gaulier, Julie Maublanc, Florence Lamballais, Sophie Bargel, Gérard Lachâtre
Forensic Science International Volume 218, Issues 1–3, 10 May 2012, Pages 25-27
Abstract

Lysergic acid diethylamide (LSD) is a potent hallucinogen, active at very low dosage and its determination in body fluids in a forensic context may present some difficulties, even more so in hair. A dedicated liquid chromatography–electrospray-tandem mass spectrometry (LC–ES-MS/MS) assay in hair was used to document the case of a 24-year-old man found dead after a party. Briefly, after a decontamination step, a 50 mg sample of the victim's pubic hair was cut into small pieces (<1 mm length), and incubated overnight in 3 mL of phosphate buffer pH 5 at room temperature. After a liquid–liquid extraction (dichloromethane/ether), the extract was analyzed using a LC–ES-MS/MS method exhibiting a limit of quantification of 0.5 pg/mg for LSD. A LSD concentration of 0.66 pg/mg of pubic hair was observed. However, this result remains difficult to interpret owing to the concomitant LSD presence in the victim's post mortem blood and urine, the lack of previously reported LSD concentrations in hair, and the absence of data about LSD incorporation and stability in pubic hair.

Uhm. Okay. Who drew the short straw and got to pluck a dead man's pubes?
 
2-(3-methylthiophenyl)-2-ethylaminocyclohexanone.png


WILFORD
2-(3-methylthiophenyl)-2-ethylaminocyclohexanone

A la recherche du temps purdu...{/I]
 
reading 3-methylthiophenyl made me think of this:
5SlO6D1.png

2-(ethylamino)-2-(3-methylthiophen-2-yl)cyclohexan-1-one
 
Not a study as such, but, a Youtuber I sometimes watch for his creative medical reviews posted a case study of a poor 19-year old who had a wild trip on a crazy overdose of nutmeg. (Nutmegs? Nuts meg. Whatever works.)



Complaints of elves bearing gifts of canned carrots and/or transforming into pickles. Heh.

He even mentions the longstanding theory that Shulgin popularized - conversion of myrsticin to amphetamines. He correctly notes there is no evidence for such transformation though.

Now, I'm an odd soul, so I find nutmeg usage in moderate amounts is enjoyable enough. I've never had negative effects of such magnitude, but then again, never took more than maybe 20 grams (whole ground fresh nuts meg) at maximum.
 
www.pnas.org

Dynamic coupling of whole-brain neuronal and neurotransmitter systems

In a technical tour de force, we have created a framework demonstrating the underlying fundamental principles of bidirectional coupling of neuronal and neurotransmitter dynamical systems. Specifically, in the present study, we combined multimodal neuroimaging data to causally explain the...
www.pnas.org www.pnas.org

Stealing this from @mr peabody ‘s neuroscience thread in his kingdom over there because it’s too cool not to share

This sort of cross-sectional fundamental neuroscience research is only in its beginnings. As the field finds its legs more and more I have a feeling we’ll uncover many more interesting ideas
 
The Therapeutic Effect of Adding Dextromethorphan to Clonidine for Reducing Symptoms of Opioid Withdrawal: A Randomized Clinical Trial
Ayyoub Malek, Shahrokh Amiri, and Bohlool Habibi Asl
ISRN Psychiatry. 2013; 2013: 546030. Published online 2013 Jun 20. doi: 10.1155/2013/546030
Background. Dextromethorphan is a noncompetitive N-methyl D-aspartate receptor antagonist that is clinically feasible for relieving the opioid withdrawal symptoms. This study compares the efficacy of a combination therapy with dextromethorphan and clonidine to treatment with clonidine alone.
Methods and Materials. In this double-blind randomized clinical trial, patients were selected from inpatients of detox and rehabilitation ward of Razi Hospital, Tabriz, Iran. They were randomly allocated to two groups receiving either clonidine (0.4–1.2 mg/day) or clonidine and dextromethorphan (300 mg/day). Withdrawal symptoms were evaluated in the first day of admission and again 24, 48, and 72 hours later.
Results. Thirty male patients completed the trial in each group. Withdrawal symptoms began to decrease in the second day in patients receiving dextromethorphan and clonidine while patients receiving clonidine experienced the more severe symptoms in 72 hours. Analysis of variance of the symptom severity score revealed a significant group × time interaction (F = 14.25; P < 0.001), so that patients receiving dextromethorphan plus clonidine had milder symptoms during three days in all of the measurements compared to clonidine group.
Conclusion. Combination therapy of dextromethorphan and clonidine would result in milder opioid withdrawal symptoms compared to clonidine alone with a reduction beginning at the second day.

Looks like getting to a 1st/low 2nd plateau dose for a few days is actually helpful in opioid w/d, despite what one might think
I guess if you can keep the cough syrup/pills down then you should give it a go, 300mg is not that high
 
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