Ketamine salts solubility

[Thou]

Well, it looks like they finally finished removing me as a mod. It was fun guys!

That's a shame. Thank you Nuke for all your smarts and wisdom

 

[sekio]

Stimulants don't effect people with ADD any differently than others
https://www.nature.com/articles/1301164

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating ‘normal’ individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well.

 

[Tzcatlipoca]

I am mostly interested in organic chemistry and my interest in pharmacology is a result of this and my interest in how our whole world works like. I've recently started studying chemistry again. I had a 3-year break due to various health problems and I didn't manage to get a master's degree. I even started studying IT during the break, but I quit it when I realised chemistry is my biggest passion and I want to learn it because it simply makes me happy. I don't really care about the money I could earn in the future, it's not a factor at all, but I'm definitely not a person who would accept an underpayment. I seriously consider staying at some university but I still have plenty of time and perhaps I will have a better opportunity to research. As I was thinking about it a few days ago, it made me kind of scared when I realised I actually hadn't planned studying chemistry again. It would be such a shame because studying IT didn't make me happy at all, it was such a tiresome duty. I'm really glad I've started changing my life so I can live the way I've always wanted. The past doesn't matter but the knowledge got through past experiences.

Why are you nervous to reveal what you study? :>

I agree completely. I would like to make acquaintance with colleagues here and offer my knowledge and experience for collaborative research

 

[clubcard]

http://bpspubs.onlinelibrary.wiley.com/hub/issue/10.1111/bph.v174.S1/

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18

 

[sekio]

Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic
Adekunle T. Bademosi, James Steeves, Shanker Karunanithi, Oressia H. Zalucki, Rachel S. Gormal, Shu Liu, Elsa Lauwers, Patrik Verstreken, Victor Anggono, Frederic A. Meunier, Bruno van Swinderen
Propofol is the most commonly used general anesthetic in humans. Our understanding of its mechanism of action has focused on its capacity to potentiate inhibitory systems in the brain. However, it is unknown whether other neural mechanisms are involved in general anesthesia. Here, we demonstrate that the synaptic release machinery is also a target. Using single-particle tracking photoactivation localization microscopy, we show that clinically relevant concentrations of propofol and etomidate restrict syntaxin1A mobility on the plasma membrane, whereas non-anesthetic analogs produce the opposite effect and increase syntaxin1A mobility. Removing the interaction with the t-SNARE partner SNAP-25 abolishes propofol-induced syntaxin1A confinement, indicating that syntaxin1A and SNAP-25 together form an emergent drug target. Impaired syntaxin1A mobility and exocytosis under propofol are both rescued by co-expressing a truncated syntaxin1A construct that interacts with SNAP-25. Our results suggest that propofol interferes with a step in SNARE complex formation, resulting in non-functional syntaxin1A nanoclusters.

http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31878-8

 

[JacksinPA]

https://www.frontiersin.org/articles/10.3389/fpsyt.2017.00152/full
Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs - Zurina Hassan1, Oliver G. Bosch2, Darshan Singh1, Suresh Narayanan3, B. Vicknasingam Kasinather1, Erich Seifritz2, Johannes Kornhuber4, Boris B. Quednow5 and Christian P. M?ller4*

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug?s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ('Kratom'), synthetic cannabinoids (e.g., 'Spice'), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.

 

[LucidSDreamr]

Stimulants don't effect people with ADD any differently than others
https://www.nature.com/articles/1301164

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating ?€˜normal?€™ individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well.

People love to say otherwise

 

[sekio]

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2.13 (95% credible interval [CrI] 1.89-2.41) for amitriptyline and 1.37 (1.16-1.63) for reboxetine. For acceptability, only agomelatine (OR 0.84, 95% CrI 0.72-0.97) and fluoxetine (0.88, 0.80-0.96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1.30, 1.01-1.68). When all trials were considered, differences in ORs between antidepressants ranged from 1.15 to 1.55 for efficacy and from 0.64 to 0.83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1.19-1.96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0.51-0.84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0.43-0.77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1.30-2.32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext

Very interesting.

 

[Vickki1000]

The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Developmen

[FONT=.SF UI Text][FONT=.SFUIText]Thoughts? The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions[/FONT][/FONT]
[FONT=.SF UI Text][FONT=.SFUIText]http://www.cell.com/cell-reports/fulltext/S2211-1247(18)30189-X[/FONT][/FONT]

 

[Cotcha Yankinov]

I think alpha2delta and NMDAr upregulation aren't the end all be all of neuropathic pain but they're certainly important

 

[Vickki1000]

I agree Gabapentin certainly not the end all of much of anything. This study was just released publicly and I thought the new MOA associated with NMDA/NMDAR was interesting. Thoughts?

 

[Nagelfar]

The Scientific Paper Is Obsolete. James Somers.

The Scientific Paper Is Obsolete. James Somers.

Because of a bit of what we're doing here, I am sure.

 

[S.J.B.]

A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval
Corresponding authors: Gert Lubeck, Jana Aradska (Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria)
Behavioural Brain Research 2018, Volume 343, Pages 83-94
Published online February 1st, 2018
https://doi.org/10.1016/j.bbr.2018.01.032

Abstract:

Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 uM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions.

 

[S.J.B.]

Synthesis and Pharmacological Evaluation of Novel C‑8 Substituted Tetrahydroquinolines as Balanced-Affinity Mu/Delta Opioid Ligands for the Treatment of Pain
Corresponding author: Henry I. Mosberg (Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Michigan, United States)
ACS Chemical Neuroscience 2018, Volume 9, Issue 7, Pages 1840-1848
Published online April 20th, 2018
https://doi.org/10.1021/acschemneuro.8b00139

Abstract:

The use of opioids for the treatment of pain, while largely effective, is limited by detrimental side effects including analgesic tolerance, physical dependence, and euphoria, which may lead to opioid abuse. Studies have shown that compounds with a mu-opioid receptor (MOR) agonist/delta-opioid receptor (DOR) antagonist profile reduce or eliminate some of these side effects including the development of tolerance and dependence. Herein we report the synthesis and pharmacological evaluation of a series of tetrahydroquinoline-based peptidomimetics with substitutions at the C-8 position. Relative to our lead peptidomimetic with no C-8 substitution, this series affords an increase in DOR affinity and provides greater balance in MOR and DOR binding affinities. Moreover, compounds with carbonyl moieties at C-8 display the desired MOR agonist/DOR antagonist profile whereas alkyl substitutions elicit modest DOR agonism. Several compounds in this series produce a robust antinociceptive effect in vivo and show antinociceptive activity for greater than 2 h after intraperitoneal administration in mice.

Table 2. Effects of Alkyl and Halogen Substitutions on Affinity, Potency, and Efficacy

NSFW:

Table 3. Effects of Aryl, Carbonyl, and Amino Substitutions on Affinity, Potency, and Efficacy

NSFW:

Most of the compounds were tested for antinociceptive activity in vivo via the mouse warm water tail withdrawal test (10 mg/kg, intraperitoneal injection). Compounds 7b, c, e, and n were found to be fully efficacious, 7f was partially active, and the others has no activity.

---

It is worth noting that there is an FDA-approved drug for irritable bowel syndrome, eluxadoline, which combines MOR agonism with DOR antagonism:

Has anyone had the chance to encounter this compound? If so, how does it compare to other opioids?

 

[sekio]

No level of alcohol consumption improves health
Robyn Burton, Nick Sheron
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31571-X/fulltext

The conclusions of the study are clear and unambiguous: alcohol is a colossal global health issue and small reductions in health-related harms at low levels of alcohol intake are outweighed by the increased risk of other health-related harms, including cancer. There is strong support here for the guideline published by the Chief Medical Officer of the UK who found that there is “no safe level of alcohol consumption”. The findings have further ramifications for public health policy, and suggest that policies that operate by decreasing population-level consumption should be prioritised.

 

[S.J.B.]

Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents
Corresponding author: Thomas M. Tzschentke (Department of Pharmacology, Grunenthal GmbH, Aachen, Germany)
Addiction Biology 2018, Volume 23, Issue 5, Pages 1010-1019
Published online September 25th, 2017
https://doi.org/10.1111/adb.12550

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ‐opioid peptide (MOP) receptors, the present study evaluated opioid‐type physical dependence produced by cebranopadol in mice and rats. In a naloxone‐precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4‐week subacute administration. Naloxone‐precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1‐week re‐administration following the spontaneous withdrawal period. In both tests, cebranopadol‐treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid‐type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.

Cebranopadol:

It was in Phase III trials as early as 2014, but I can't find any news to indicate that it has been approved (or rejected) by the FDA yet.

 

[S.J.B.]

Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway
Corresponding author: Leyre Uriguen (Department of Pharmacology, University of the Basque Country, Leioa, Spain)
Neuropsychopharmacology 2018, Volume 43, Pages 2028–2035
Published online April 27th, 2018
https://doi.org/10.1038/s41386-018-0076-y

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

 

[sekio]

Indirect modulation of the endocannabinoid system by specific fractions of nutmeg total extract
Abir T. El-Alfy, Sharon Joseph, Akshar Brahmbhatt, Setor Akati & Ehab A. Abourashed
https://www.tandfonline.com/doi/full/10.1080/13880209.2016.1194864

Objective: The study evaluates nutmeg fractions for binding capacity with various CNS receptors and their potential interaction with the endocannabinoid system.

Materials and methods: Dichloromethane (DF) and ethyl acetate (EF) fractions were prepared from the methanol extract of powdered whole nutmeg. The HPLC-profiled fractions were assayed by the NIMH Psychoactive Drug Screening Program (PDSP) in a panel of CNS targets at a 10 μg/mL concentration. The fractions were also screened for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition, initially at a concentration of 500 μg/mL, then by concentration-dependent inhibition studies.

Results: None of the tested fractions showed significant binding to CNS receptors included in the PDSP panel. However, both fractions exerted significant inhibition of the FAAH and MAGL enzymes. The DF fraction inhibited FAAH and MAGL enzymes at IC50 values of 21.06 ? 3.16 and 15.34 ? 1.61 μg/mL, respectively. Similarly, the EF fraction demonstrated FAAH and MAGL inhibition with IC50 values of 15.42 ? 3.09 and 11.37 ? 6.15 μg/mL, respectively.

nutmeg is a FAAH inhibitor??? trippy

 

[S.J.B.]

Methamphetamine Induces Dopamine Release in the Nucleus Accumbens Through a Sigma Receptor-Mediated Pathway
Corresponding author: Scott C. Steffensen (Department of Psychology and Neuroscience, Brigham Young University, Provo, United States)
Neuropsychopharmacology 2018, Volume 43, Pages 1405–1414
Published online November 29th, 2017
https://doi.org/10.1038/npp.2017.291

Methamphetamine (METH) is a drug with a high addictive potential that is widely abused across the world. Although it is known that METH dysregulates both dopamine transmission and dopamine reuptake, the specific mechanism of action remains obscure. One promising target of METH is the sigma receptor, a chaperone protein located on the membrane of the endoplasmic reticulum. Using fast-scan cyclic voltammetry, we show that METH-enhancement of evoked dopamine release and basal efflux is dependent on sigma receptor activation. METH-induced activation of sigma receptors results in oxidation of a cysteine residue on VMAT2, which decreases transporter function. Unilateral injections of the sigma receptor antagonist BD-1063 prior to METH administration increased dopamine-related ipsilateral circling behavior, indicating the involvement of sigma receptors. These findings suggest that interactions between METH and the sigma receptor lead to oxidative species (most likely superoxide) that in turn oxidize VMAT2. Altogether, these findings show that the sigma receptor has a key role in METH dysregulation of dopamine release and dopamine-related behaviors.

 

[S.J.B.]

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists
Corresponding author: Lorella Pasquinucci (Medicinal Chemistry Section, Department of Drug Sciences, University of Catania, Catania, Italy)
Molecules 2018, Volume 23, Issue 3, Page 677
Published online March 16th, 2018
https://doi.org/10.3390/molecules23030677

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.

NSFW: