• N&PD Moderators: Skorpio | thegreenhand

⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

So here it's looking at the transporter affinity only but we know the primary action of MDMA, for example is as a releaser.

This means that the transporter affinities are a middle value where they can cause release without shutting down the transporter and preventing release into the synapse?
 
No, I think affinity for the transporter protiens is unrelated toi the ability of drugs to reverse transport. For instance drugs like citalopram have a humongous affinity for SERT but do not cause release, and drugs like MDMA have compartatively less affinity but elevate serotonin concentrations much more effectively.
 
Preclinical Safety Assessment of the 5-HT2A Receptor Agonist PET Radioligand [11C]Cimbi-36

Progress on use of 25B-NBOMe as a radioligand for PET scanning

[11C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT2A) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT2A receptors and may have the potential to quantify changes in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [11C]Cimbi-36, including radiation dosimetry and in vivo pharmacology.
 
Not that recent, but reading the story in pd of some guy going blind after tripping had me remembering it.
http://www.ncbi.nlm.nih.gov/pubmed/19221973
[Recurrent cortical blindness after LSD-intake].

Recurrent disturbances of vision associated with headaches are typical signs of a migraine. A 15-year-old girl suffered from common migraine. The patient had a headache and nausea five days after a first and proved intake of LSD. Shortly later, a complete blindness of both eyes developed within seconds. These symptoms continued for 48 hours. As the pupillar reactions were intact the findings were consistent with cortical blindness. MRI and MR-angiography of the brain, analysis of the cerebrospinal fluid and blood investigations for thrombophilia were normal. The EEG showed a bilateral symmetrical delta wave slowing over the occipital areas. Within the following three months the girl had three more episodes with complete blindness over a period of 12-36 hours. There have never been any visual disturbances in between the episodes and afterwards. Extended diagnosis with long term blood pressure measurement, Doppler sonography and visual evoked potentials were normal. The occipital slowing in the EEG persisted for 18 months. As the symptoms were unusually long and severe for a complicated migraine it is possible that the temporary blindness was the correlate of flash backs caused by the LSD. LSD intake could trigger additional, local cortical dysfunction (e. g. in the occipital areas) in preexisting migraine.
 
This review is almost a year old now, but I saw there was some interest in depressogenic substances so I'll just leave this here.

CB1 receptor antagonists: new discoveries leading to new perspectives.
http://www.ncbi.nlm.nih.gov/pubmed/22463610

Abstract
CB(1) receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.
 
Design, Synthesis, and Pharmacological Characterization of N- and O-Substituted 5,6,7,8-Tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol Analogues: Novel 5-HT2A/5-HT2C Receptor Agonists with Pro-Cognitive Properties
http://dx.doi.org/10.1021/jm301656h

Interesting new scaffold for 5-HT2A/2C agonists.

The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABAA and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT2A and 5-HT2C receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT2C antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT2A and/or 5-HT2C receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.
jm-2012-01656h_0010.gif
 
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i found some neat papers on Tocris' website.

http://www.tocris.com/pdfs/pdf_downloads/receptor_binding_review.pdf - Review on Ki and how it is measured, receptor binding, etc

http://www.tocris.com/pdfs/pdf_downloads/5-HT_Receptors_Review.pdf - Tocris Bioscience review on the serotonin receptors (5ht 1 family, 5ht2family, & 5ht3)
http://www.tocris.com/pdfs/pdf_downloads/dopamine_receptors_review.pdf - Dopamine receptors
http://www.tocris.com/pdfs/pdf_downloads/gaba_receptors_review.pdf - GABA, benzos, neuroactive steroids.
http://www.tocris.com/pdfs/pdf_downloads/opioid_receptors_review.pdf - Opioids
http://www.tocris.com/pdfs/pdf_downloads/melatonin_receptors_review.pdf - Melatonin MTx receptors
 
Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT2A) receptor activity via ERK1/2 signaling

Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans.
 
A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill)health. Legal highs or illegal highs?

A total of 22 products were purchased from five different internet sites, 18 months after the UK ban on substituted cathinones, like mephedrone, was introduced in April 2010. Each substance was screened to determine its active ingredients using accepted analytical techniques.

Despite amendments to legislation, prohibited class B substances are still readily available in large quantities over the internet. The findings suggest that these prohibited substances are being manufactured or imported into the UK on a large scale, which has serious implications for public health and clinicians who are ill equipped to deal with this newly emerging problem.

A case of 25I-NBOMe (25-I) intoxication: a new potent 5-HT2A agonist designer drug


Abuse of synthetic stimulant compounds resulting in significant toxicity is being increasingly reported by poison centers. Toxicologic assessment is complicated by inconsistent manufacturing processes and limited laboratory testing. We describe a case of self-reported exposure to 25-I (25I-NBOMe), a novel phenethylamine derivative, with subsequent quantification in serum. Case details. An 18-year-old male presented to the emergency department (ED) with severe agitation and hallucinations after jumping out of a moving car. He was tachycardiac (150–160 bpm) and hypertensive (150–170 mm Hg systolic and 110 mg Hg diastolic), and required physical restraints and treatment with intravenous lorazepam administration. His symptoms gradually improved and vital signs returned to normal over 48 h, though he continued to have episodes of aggressiveness.

An assay was developed by our analytical toxicology laboratory for 25-I, and serum obtained during ED evaluation and treatment was found to contain 0.76 ng/ml of 25-I. Case discussion. For 25I-NBOMe, 25-I is a common abbreviation for 25I-NBOMe, which is a (n-benzyl) phenethylamine in the 2C “family.”Initially synthesized for research, cases of self-reported use of 25-I have recently appeared in the literature, some of which contain qualitative urine confirmation. There are no commercially available quantitative assays, and no previous reports have published serum concentrations. 25-I is a potent new synthetic drug with apparent significant behavioral toxicity that can be detected and quantified in serum.
 
MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus.

Abstract

The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10 mg/kg, i.p. at 2 h intervals) resulted in a 2-3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100 μM) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus.
 
Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT2A) receptor activity via ERK1/2 signaling

Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans.

Can anybody upload it?
 
Not a "recent" article, but haven't see this posted...

Nature said:
On a small table in his office at the Scripps Research Institute in La Jolla, California, Ray Stevens spreads out a sheet of paper covered with colourful branched lines, each sprouting and thinning before terminating in an esoteric code. “This is the dream,” he declares.

The intricate diagram represents the largest family of receptor proteins encoded in the genome — the G-protein-coupled receptors (GPCRs), ubiquitous cell-surface molecules that are activated by light, odours, hormones and neurotransmitters. Stevens wants to determine the atomic structures of receptors on all branches of the tree. This week, that goal moved two receptors closer: Stevens's group has solved the atomic structure of the κ-opioid receptor (κ-OR)1, and a team led by Brian Kobilka at Stanford University in California has solved the medically crucial μ-opioid receptor (μ-OR)2. The structures, published in Nature, bring the tally of GPCR structures solved this year alone up to five.
http://www.nature.com/news/opioid-receptors-revealed-1.10273

Apparently the MOR structure has been solved. It's confirmed that mu-opioid exists as a dimer and also that its binding pocket is rather promiscuous. The Nature guys think that may be the reason it can respond so quickly to activation/antagonism.
 
Not a "recent" article, but haven't see this posted...


http://www.nature.com/news/opioid-receptors-revealed-1.10273

Apparently the MOR structure has been solved. It's confirmed that mu-opioid exists as a dimer and also that its binding pocket is rather promiscuous. The Nature guys think that may be the reason it can respond so quickly to activation/antagonism.

Solving of GPCR crystal structures is really picking up: Here's the 5-HT1B receptor

STRUCTURAL BASIS FOR MOLECULAR RECOGNITION AT SEROTONIN RECEPTORS

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein–coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine.
 
Not a journal article but interesting anyway

Derek Lowe - Chemical probes vs drugs

A drug is defined by its effects in a living creature (I'm tempted to add "Preferably, one that is willing to pay for it"). A chemical probe, on the other hand, is defined by its specificity. It's important not to confuse the two - you can get all excited about how specific your drug candidate is, how exquisitely it hits its target, but (as we have proven over and over in this business) that means nothing if hitting that target isn't clinically meaningful. Being impressed by the specificity of a chemical probe compound, on the other hand, is entirely appropriate - but no one should think that this makes it closer to being a drug.

Makes me think about, say, the NBOMes versus LSD.
 
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