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S.J.B.

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Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor
Corresponding author: Thomas E. Prisinzano (Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, United States)
ACS Chemical Neuroscience 2020, Volume 11, Issue 12, Pages 1781–1790
Published online May 8th, 2020
https://doi.org/10.1021/acschemneuro.0c00191
Previous structure–activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-opioid receptor (MOR) agonist, kurkinorin (1), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound, 25, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, 25 is over 100× more potent than morphine and over 5× more potent than fentanyl in vitro and elicits antinociception with limited tolerance development in vivo. This is especially significant given that 25 lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.
 

S.J.B.

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Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats
Corresponding author: Richard A. Glennon (Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, United States)
ACS Chemical Neuroscience 2020, Volume 11, Issue 12, Pages 1762–1769
Published online May 1st, 2020
https://doi.org/10.1021/acschemneuro.9b00617
Methcathinone (MCAT; 1), the progenitor of numerous and widely abused “synthetic cathinone” central stimulants, exists as a pair of optical isomers. Although S(−)MCAT is several-fold more potent than R(+)MCAT in rodent locomotor stimulation and in stimulus generalization studies in rat drug discrimination assays, the individual optical isomers of MCAT have never been directly compared for their actions at monoamine transporters that seem to underlie their actions and have never been examined for their relative abuse potential. Here, we found that the isomers of MCAT are nearly equieffective at dopamine and norepinephrine transporters (DAT and NET, respectively) as transporter substrates (i.e., as releasing agents) and are ≥63-fold less potent at the serotonin transporter (SERT). In intracranial self-stimulation (ICSS) studies to evaluate abuse-related drug effects in rats, S(−)MCAT was approximately twice as potent as its R-enantiomer. Achiral analogs, α-methyl MCAT (3) and α-des-methyl MCAT (4), also were DAT/NET substrates and also produced abuse-related ICSS effects, indicating that they retain abuse potential and that they might be useful for the further study of the stereochemistry of synthetic cathinone analogs with chiral β- (or other) substituents.


Not surprisingly, alpha-des-methyl MCAT is significantly less potent as an in vitro dopamine and serotonin releaser than either of the MCAT enantiomers, although it is a roughly-equivalent norepinephrine releaser. It was also over 10 times less potent than either MCAT enantiomer in a rat self-stimulation study. However, alpha-methyl MCAT looks like it has potential. It was half as potent as racemic MCAT at DAT but twice as potent at SERT (although all compounds were only weakly active at SERT relative to DAT and NET) and had essentially identical potency to MCAT in the rat self-stimulation study.
 

sekio

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"A builder aged 29 came to the accident and emergency department having jumped down on to a 15 cm nail. As the smallest movement of the nail was painful he was sedated with fentanyl and midazolam. The nail was then pulled out from below. When his boot was removed a miraculous cure appeared to have taken place. Despite entering proximal to the steel toecap the nail had penetrated between the toes: the foot was entirely uninjured."

Ref:
Fisher JP, Hassan DT, O’Connor N. Minerva. BMJ. 1995 Jan 7;310(70).
 

polymath

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"A builder aged 29 came to the accident and emergency department having jumped down on to a 15 cm nail. As the smallest movement of the nail was painful he was sedated with fentanyl and midazolam. The nail was then pulled out from below. When his boot was removed a miraculous cure appeared to have taken place. Despite entering proximal to the steel toecap the nail had penetrated between the toes: the foot was entirely uninjured."

Ref:
Fisher JP, Hassan DT, O’Connor N. Minerva. BMJ. 1995 Jan 7;310(70).
So it was nocebo pain because he though the nail had penetrated his foot.
 

sekio

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So all I have to do is stick a nail through my sneakers and go to the emergency room to get some free narcotics IV? Hmm....
 

sekio

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Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP
Chen Xu, Junhua Zhang, Doina M. Mihai, Ilyas Washington
Journal of Cell Science 2014 127: 388-399; doi: 10.1242/jcs.134262

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.

Eat spinach salad and nap in the sun?
 
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