⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

Dresden

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Until a new Sprague Dawley rat test other than the Learned Helplessness Test of putting a rat into a column of water until it gives up on trying to swim is adopted, we will NEVER come up with an efficacious antidepressant. Flat affect is not euphoria.

SSRIs/SNRIs:
"This is not euphoria. This is not euphoria."--The Nathan Sheppard Band.
 

S.J.P.

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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.
 
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S.J.P.

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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.

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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?
 
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sekio

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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.P.

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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.
 
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S.J.P.

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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

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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.P.

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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.
 
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S.J.P.

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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:
 

sekio

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Drug-induced acute psychosis in an adolescent first-time user of 4-HO-MET
Jakob Taljemark, Bjorn Axel Johansson
Eur Child Adolesc Psychiatry (2012) 21:527–528 DOI 10.1007/s00787-012-0282-9

4-HO-MET (4-hydroxy-N-methyl-ethyltryptamine), also known as metocin, is a synthetic hallucinogenic psychedelic drug. It resembles psilocin, the hallucinogenic component found in ‘‘magic mushrooms’’ [1]. In many countries including Sweden [2], 4-HO-MET has not yet been classified as an illicit substance, and can be ordered on the internet as a so-called ‘‘legal high’’. We describe a case where an adolescent presenting with apathy and mutism was later diagnosed with a drug-induced acute psychosis after inhalation of 4-HO-MET. ‘‘B’’, a 17-year-old boy living with his parents, was vadmitted to the acute medical department after being found by police, wandering along a motorway in his underwear. He expressed to the policemen that ‘‘I will not talk to anyone’’ and then remained mute and apathetic. [...] On admission, blood tests and a CT head scan were conducted, showing no significant abnormalities. A bedside urinary toxicology screen was positive for THC and cocaine, but no further analysis was done. ‘‘B’’ received supportive care. On the evening of admission, after being apathetic all day, he suddenly took his own discharge. He was soon found outside the hospital, having jumped 3–4 m from a roof. [...] On the day of discharge, 11 days after hospital admission, a mental state examination indicated no ongoing psychiatric illness, and ‘‘B’’ disclosed the entirety of his story. He had received 4-HO-MET powder from a friend who had ordered the drug over the internet. ‘‘B’’ inhaled approximately 100 mg of 4-HO-MET on the evening before admission. He soon started seeing doors in the bookcase in front of him. In panic he left the apartment. He walked the streets that he experienced as under a metre of water and filled with snakes. He felt distressed, lonely and persecuted. He sensed insects under his skin and his heart jumping out of the chest. ‘‘B’’ remembered being admitted to hospital and inside his head he heard his father’s voice repeating ‘‘you have never dared to dive’’. He therefore escaped from the ward, climbed onto a roof and ‘‘dived’’ to prove his father wrong.
So, uh, respect the mushroom. Or you'll be found wandering along a highway clad only in your skivvies, then throw yourself off a hospital roof.

Also, 100mg of psilocin or its analogs is too much.
 

DotChem

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Subjective effectiveness of ibogaine treatment for problematic opioid consumption: Short- and long-term outcomes and current psychological functioning.
Davis AK1, Barsuglia JP2, Windham-Herman AM3, Lynch M2, Polanco M2.
1Department of Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit, Johns Hopkins School of Medicine, Baltimore, MD, USA.2 Crossroads Treatment Center, Rosarito, Mexico.3 Yale School of Medicine, New Haven, CT, USA.

Abstract

Background and aims:
Very few studies have reported the effectiveness of ibogaine as a treatment for chronic opioid use. Therefore, this study evaluated the acute subjective effects of ibogaine, outcomes on problematic opioid consumption, and the long-term associations with psychological functioning.

Methods:

Using online data collection, 88 patients who received ibogaine treatment in Mexico between 2012 and 2015 completed our survey.

Results:

Most participants (72 percent) had used opioids for at least 4 years and 69% reported daily use. Most (80.0% ) indicated that ibogaine eliminated or drastically reduced withdrawal symptoms. Fifty percent reported that ibogaine reduced opioid craving, some (25 percent)reporting a reduction in craving lasting at least 3 months. Thirty percent of participants reported never using opioids again following ibogaine treatment. And over one half (54 percent) of these abstainers had been abstinent for at least 1 year, with 31% abstinent for at least 2 years. At the time of survey, 41% of all participants reported sustained abstinence (>6 months). Although 70% of the total sample reported a relapse following treatment, 48% reported decreased use from pretreatment levels and an additional 11% eventually achieved abstinence. Treatment responders had the lowest rates of depressive and anxious symptoms, the highest levels of subjective well-being and rated their ibogaine treatment as more spiritually meaningful compared with treatment non-responders.

Conclusion:

The results suggest that ibogaine is associated with reductions in opioid use, including complete abstinence, and has long-term positive psychological outcomes. Future research should investigate the efficacy of ibogaine treatment using rigorous longitudinal and controlled designs.


KEYWORDS:

effectiveness; heroin; ibogaine; outcomes; prescription opioids
 
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S.J.P.

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Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias
Corresponding author: Thomas D. Bannister (Department of Chemistry, The Scripps Research Institute, Jupiter, United States)
Journal of Medicinal Chemistry 2018, Volume 61, Issue 19, Pages 8895-8907
Published online September 10th, 2018
https://doi.org/10.1021/acs.jmedchem.8b01136

While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal βarrestin-mediated signaling because MOR agonist-treated βarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/βarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.
NSFW:


 

DotChem

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Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile
Gonz?lez J1, Prieto JP2, Rodr?guez P3, Cavelli M1, Benedetto L1, Mondino A1, Pazos M3, Seoane G3, Carrera I3, Scorza C2, Torterolo P
Frontiers in Pharmacology. 2018 Apr 27;9:374. doi: 10.3389/fphar.2018.00374. eCollection 2018

ABSTRACT

Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed.The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression.In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.


KEYWORDS: REM sleep; hallucinogens; ibogaine; psychedelics; wakefulness
 
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S.J.P.

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Abuse Potential of Biased Mu Opioid Receptor Agonists
Corresponding author: S. Stevens Negus (Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, United States)
Trends in Pharmacological Sciences 2018, Volume 39, Issue 11, Pages 916-919
Published online October 18th, 2018
https://doi.org/10.1016/j.tips.2018.08.007

G protein-biased mu opioid receptor (GPB-MOR) agonists constitute an emerging class of opioid analgesics. The first-in-class GPB-MOR agonist TRV130 (oliceridine) produces typical opioid-like abuse-related effects in rodents and humans. Although GPB-MOR agonists may be safer than conventional opioids on some endpoints, prevailing evidence suggests that they will retain opioid-like abuse potential.
Remember oliceridine?



It was all over the news as an up-and-coming "low abuse potential" opioid, but it looks like both animal studies and a human trial indicate otherwise.
 

S.J.P.

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Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT6 Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo
Corresponding author: Jadwiga Handzlik (Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, Cracow, Poland)
Molecules 2018, Volume 23, Issue 10, Page 2529
Published online October 3rd, 2018
https://doi.org/10.3390/molecules23102529

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT6, 5-HT1A, 5-HT2A, 5-HT7, and dopamine D2 receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT6 receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds (18 and 26) were identified as the most active 5-HT6R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, the most active one in the series (5-HT6R: Ki = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6–197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for 18 and 26, respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.
NSFW:
 

AlphaMethylPhenyl

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Chronic oxycodone induces axonal degeneration in rat brain


Opioids aren't so physically healthy on their own. We're going to see a windfall of these kind of studies in not too long. The government no longer sanctions huge doses of opioids over long periods of time, or at least is getting there.

We're talking

1. Apparently maladaptive apoptosis
2. Demyelination, leading to apoptosis/necrosis more likely

From: an increased stress response.
 

sekio

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Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants
Deirdre M. McCarthy, Thomas J. Morgan Jr., Sarah E. Lowe, Matthew J. Williamson, Thomas J. Spencer, Joseph Biederman, Pradeep G. Bhide
https://doi.org/10.1371/journal.pbio.2006497 | PLoS Biol 16(10): e2006497. (2018)
Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naive females to produce the F1 generation. Male and female F1 mice were bred with drug-naive partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.
This is pretty scary... nicotine doesn't only cause changes in your DNA, but also your future kids' DNA, and even your future grandkids' DNA... just imagine what some of the other crap in tobacco smoke will do.

I don't think I could find a better reason to encourage people to stop nicotine use (or I guess save it for people who are going to remain celibate, or have already had children) - habitual smoking effecting your whole family lineage sounds like some made up toxin out of a bad sci-fi movie, or a curse or something, but it's actually a thing. Makes you wonder whether the prevalence of smoking in the '50s led to the next generations of kids being as they are (boomers and afterwards) ....
 
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AlphaMethylPhenyl

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That said, it's always a task to differentiate the studies on nicotine from those on the tobaccy. They're way too often conjoined and thought of as one. Commercial tobacco and nicotine are different. It's like weed isn't CBD or THC.
 

polymath

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So looks like there is some actual proof about the harmful effects of nicotine itself... Is this some unspecific effect of nicotine or is it a direct result of binding to nicotinic receptors? Another nicotine agonist that is found in nature is the arecoline in Betel nut, but that compound is also a muscarine agonist to some extent.
 
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