• N&PD Moderators: Skorpio | thegreenhand

⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum.

http://www.ncbi.nlm.nih.gov/pubmed/22191803

seems Mephedrone is not so neurotoxic as everyone thought.

While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels.
 
Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands

Based on the structure of the superpotent 5-HT2A agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogs to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely-substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT2A over the 5-HT2C receptor, making it the most selective 5-HT2A receptor agonist ligand currently known.

The latest in 5-HT2A agonists from Dave Nichols & Co.
 
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Cool. D. Nichols points out that even the best ring-constrained analog is less potent than 25BNBOMe though
 
Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum.

http://www.ncbi.nlm.nih.gov/pubmed/22191803

seems Mephedrone is not so neurotoxic as everyone thought.

I'm really not that surprised. David Nutt pointed out that since Mephedrone became available cocaine related deaths in the UK plummeted while Mephedrone related deaths are comparatively nonexistent, so at least in his opinion Mephedrone is far less toxic than cocaine overall.
 
Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux.

http://www.ncbi.nlm.nih.gov/pubmed/22722938

Free Full Text!
Some great reading about the intracellular mechanisms that mediate amphetamine's DAT reversal, it also suggests that there is a far more complex interplay within the cell resulting in the cascade leading to PKC-Beta's phosphorylation of Thr53.

Must resist urge to look up known modulators of DAT and interactions of mentioned proteins... Must study for MCAT...
 
Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299 (2005; a little old I know, but worth mentioning)
Free full text: http://www.pnas.org/content/102/48/17489.full.pdf

SNAP 37889
snap37889.gif
, SNAP 398299
snap398299.gif

Administration of these two compounds (per the oral route) results in acute antidepressant/anxiolytic effects in mice/guinea pigs. Anxiolytic activity for SNAP 37889 begins at 0.3mg/kg is strong at 5mg/kg up to 30mg/kg, comparable to 5mg/kg of the benzodiazepine chlordiazepoxide at the highest dose level. Effective dose in humans if bioavailability via the oral route is good would then scale at a guesstimate to be 1-25mg. References for the synthesis of these molecules is given.
 
Exploration of Novel 3-Substituted Azetidine Derivatives As Triple Reuptake Inhibitors
http://pubs.acs.org/doi/abs/10.1021/jm3008294

jm-2012-008294_0004.gif

Novel azetidines based on the 3-aryl-3-oxypropylamine scaffold were designed, synthesized, and evaluated as TRIs. Reduction of 1 followed by Swern oxidation and then Grignard reaction gave 3. The alkylation of 3 provided the corresponding azetidine derivatives 6, of which the two most promising, 6bd and 6be, were selected from 86 prepared analogues based on their biological profiles. Compound 6be showed activity in vivo in FST at 10 mg/kg IV or 20–40 mg/kg PO.
 
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Can anyone get this paper:

The treatment outcome of psychotic disorders by traditional healers in central Sudan.
Sorketti EA, Zainal NZ, Habil MH.

Abstract
BACKGROUND:
Alternative and traditional healing methods are common and popular in Sudan, particularly for treating people with mental disorders, but little information is available about the outcome of theses traditional healing approaches.

OBJECTIVES:
To study the outcome of treating patients with psychotic disorders by traditional healers, and to understand the type of services, interventions procedures and treatments methods used by traditional healers to manage patients with psychotic disorders.

METHOD:
A prospective follow-up quantitative study of a cohort of inpatients with psychotic disorders was carried out from admission until discharge. Subjects were people with psychotic disorders undergoing treatment in traditional healer centres in central Sudan. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose the psychotic disorders and the Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms on admission and discharge from the traditional healer centre.

RESULTS:
We interviewed 129 inpatients with psychotic disorders on admission and discharge from the traditional healers centres. There was a significant reduction in the PANSS score (p = .0001) after a mean period of stay of 4.5 months. The mean for the overall PANSS score was 118.36 on admission and 69.36 on discharge.

CONCLUSION:
Although traditional-healing approaches produce a significant improvement in the signs and symptoms of psychotic disorders measured on the PANSS, they need to be further investigated, assessed and studied.

Pubmed
Article link
 
Can anyone get this paper:

The treatment outcome of psychotic disorders by traditional healers in central Sudan.
Sorketti EA, Zainal NZ, Habil MH.

Abstract
BACKGROUND:
Alternative and traditional healing methods are common and popular in Sudan, particularly for treating people with mental disorders, but little information is available about the outcome of theses traditional healing approaches.

OBJECTIVES:
To study the outcome of treating patients with psychotic disorders by traditional healers, and to understand the type of services, interventions procedures and treatments methods used by traditional healers to manage patients with psychotic disorders.

METHOD:
A prospective follow-up quantitative study of a cohort of inpatients with psychotic disorders was carried out from admission until discharge. Subjects were people with psychotic disorders undergoing treatment in traditional healer centres in central Sudan. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose the psychotic disorders and the Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms on admission and discharge from the traditional healer centre.

RESULTS:
We interviewed 129 inpatients with psychotic disorders on admission and discharge from the traditional healers centres. There was a significant reduction in the PANSS score (p = .0001) after a mean period of stay of 4.5 months. The mean for the overall PANSS score was 118.36 on admission and 69.36 on discharge.

CONCLUSION:
Although traditional-healing approaches produce a significant improvement in the signs and symptoms of psychotic disorders measured on the PANSS, they need to be further investigated, assessed and studied.

Pubmed
Article link

Try this
 
Ronald S. Duman, George K. Aghajanian
Synaptic Dysfunction in Depression
Science 5 October 2012: Vol. 338 no. 6103 pp. 68-72
DOI: 10.1126/science.1222939

Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-d-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.
 
J Ethnopharmacol. 2010 Mar 2;128(1):160-5. Epub 2010 Jan 11.
The memory-enhancing effects of Euphoria longan fruit extract in mice.
AIM OF THE STUDY:

The fruit of Euphoria longan (Lour.) Steud. (Sapindaceae) is sweet and edible. Dried Euphoria longan fruit is prescribed as a tonic and for the treatment of forgetfulness, insomnia, or palpitations caused by fright in traditional Chinese medicine. The effects of aqueous extract of Euphoria longan fruit (ELE) on learning and memory and their underlying mechanisms were investigated.
MATERIALS AND METHODS:

Aqueous extract of Euphoria longan fruit (ELE) was administered to ICR mice for 14 days. Piracetam was used as a positive control for its known memory-enhancing effects. Memory performances were assessed using the passive avoidance task. The expressions of phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and the incorporation of 5-bromo-2-deoxyuridine (BrdU) in hippocampal dentate gyrus and CA1 regions were investigated using immunohistochemical methods.
RESULTS:

The step-through latency in the ELE-treated group was significantly increased compared with that in the vehicle-treated controls (P<0.05) in the passive avoidance task. Piracetam-treated group also showed enhanced cognitive performaces in the passive avoidance task. Immunohistochemical studies revealed that the number of cells immunopositive for BDNF, pCREB, or pERK 1/2 was significantly increased in the hippocampal dentate gyrus and CA1 regions after ELE treatment for 14 days (P<0.05). DCX and BrdU immunostaining also revealed that ELE significantly enhanced immature neuronal survival, but not neuronal cell proliferation in the subgranular zone of the dentate gyrus.
CONCLUSIONS:

The present results suggest that subchronic administration of aqueous extract of Euphoria longan fruit enhances learning and memory, and that its beneficial effects are mediated, in part, by BDNF expression and immature neuronal survival.
 
trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT2 receptor family

Cyclopropyl analogues of DOB and DOI by Nichols et al.

Abstract

A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2 family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (−)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses – although (−)-4 and (−)-5 may be useful as tools to probe 5-HT2 receptor function – one would need to be mindful that their selectivity for 5-HT2A receptors is somewhat less than for DOI itself.

Keywords: cyclopropanation; diazomethane; hallucinogen; 5-HT2A agonist; receptor probe; trans-2-phenylcyclopropylamines
 
DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice.

Abstract
Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2-carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.


Naloxone potentiates the disruptive effects of mescaline on operant responding in the rat.
Abstract
Food-deprived male rats were trained to press a lever on a fixed ratio-40 (FR-40) operant schedule for food reinforcement. Administration of mescaline (4.0--10.0 mg/kg) immediately before the start of the operant session resulted in a cessation of responding for some portion of the 40-min period ("hallucinatory pause"). The duration of this pause was found to be dose-dependent. Although administration of naloxone alone (1.0-8.0 mg/kg, five minutes prior to the start of the session) had no effect on FR-40 responding per se, pretreatment with this agent significantly potentiated the disruptive effects of mescaline. This potentiation by naloxone was further shown to be dose-dependent. These data suggest that the effects of the phenethylamine hallucinogen mescaline are potentiated by pretreatment with the narcotic antagonist naloxone.
 
Confirmation that there is a genetically linked component to cannabis psychosis susceptibility

In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. [...] Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers.

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(12)00555-0/abstract

just goes to show how deep biochemistry is.
 
http://www.sciencedirect.com/science/article/pii/S0014299912010114

Fourteen substances from the class of drugs sometimes known as “legal highs” were screened against a battery of human receptors in binding assays, and their potencies as inhibitors of monoamine uptake determined in functional in vitro assays.

Thirteen of the test substances acted as inhibitors of monoamine uptake at submicromolar concentrations, including 9 potent inhibitors of the dopamine transporter (DAT), 12 potent inhibitors of the norepinephrine transporter (NET) and 4 potent inhibitors of the serotonin transporter (SERT). Seven compounds acted as submicromolar inhibitors of both DAT and NET, and three substances 1-(benzofuran-5-yl)propan-2-amine (5-APB), 1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one hydrochloride (“naphyrone”) and 1-naphthalen-1-yl-2-pyrrolidin-1-ylpentan-1-one hydrochloride (“1-naphyrone”) were submicromolar inhibitors of all three monoamine transporters.

There was a lack of correlation between results of functional uptake experiments and in vitro binding assays for the monoamine transporters. There was also no correlation between the human behavioral effects of the substances and the results of bindings assays for a range of receptor targets, although 1-(benzofuran-5-yl)propan-2-amine (5-APB), 1-(benzofuran-6-yl)propan-2-amine hydrochloride (6-APB) and 5-iodo-2,3-dihydro-1H-inden-2-amine hydrochloride (5-iodo-aminoindane) exhibited <100 nM affinities for 5HT2B and α2C receptors. Functional assays revealed that 5-APB and 6-APB were potent full agonists at 5HT2B receptors.
 
Functional assays revealed that 5-APB and 6-APB were potent full agonists at 5HT2B receptors.

Not good for the ol' heart valves then?
 
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