A Word to the Wise about Ketamine


Major depressive disorder (MDD), also known simply as depression, and its impact on functioning and well-being has been compared to that of other chronic medical conditions such as diabetes. The World Health Organization estimates depression as the fourth highest burden of disease in the world1 .

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Figure 1: Proposed neurobiological model of depression2

Prolonged stress and depression alter prefrontal glutamate release and reduce glutamate uptake, leading to increased extracellular glutamate and excitotoxicity3. High levels of extracellular glutamate precipitates neuronal atrophy through dendritic retraction4, reduced dendritic arborization5, and reduced synaptic strength. An example of the effect of prolonged stress on dendritic arborization and length in rats is shown on the right (Fig. 1).

Research on antidepressants has achieved little success in developing fundamentally novel antidepressant mechanisms, leaving psychiatrists with relatively few pharmacologic options. Several antidepressants that are currently in use are mainly targeting the monoaminergic system where substantial numbers of patients are failing to achieve a sustained remission6. Moreover, conventional antidepressants are only beneficial when prescribed over a long- term period. It is clear that we are in urgent need to find a rapidly acting antidepressant with robust efficacy in patients who are resistant to traditional antidepressants.

Sri 2Ketamine is a drug used illicitly as a hallucinogen and was first tested in humans in 1964. It was approved 1970 in the USA as a surgical anaesthesia that was used in Vietnam War due to its safety7. Ketamine can be a prototype for the new generation of antidepressants by showing good efficacy in patients who are refractory to the existing treatments. Low dosages of ketamine reduce depression symptoms within 4 hours of intravenous administration in severely treatment-resistant depressed patients8.

Ketamine exhibits promising antidepressant effects even in patients with bipolar disorder and patients with severe symptoms that did not respond to ECT9. A critical obstacle to the broader study and implementation of ketamine treatment for depression is the lack of clarity as to how to sustain its antidepressant effects. Pilot studies suggest that ketamine may be sustained by repeated intermittent administration with persistence of the antidepressant effects for longer periods in some patients10.

Briefly, ketamine works by enhancing synaptic plasticity (mechanism through which neural circuits regulate their excitability and connectivity) through regulating AMPA and NMDA receptors.

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Figure 2: Prefrontal synaptic connectivity during normal mood, depression, and after remission (Abbreviations: ⦿, activate; ∅, block; , decrease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; GABA, γ-aminobutyric acid; mTORC1, mammalian target of rapamycin complex 1.)

There have been some clinical trials where ketamine shows acute efficacy 11 in treating TRD (treatment resistant depression) , bipolar depression12 and major depressive disorder with suicidal ideation13, but the number of subjects in these trials ranges from 20 to 57 patients. Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System (FAERS) revealed that patients who received ketamine had a significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain14.

It is encouraging that FAERS makes a case for study of ketamine as a psychiatric drug but there are financial and ethical obstacles for a larger scale clinical trial to validate further the safety and efficacy of Ketamine. To date, Ketamine is not only the most extensively studied NMDA antagonist, with 12 published randomized clinical trials, but is the only NMDA antagonist to date consistently demonstrating antidepressant efficacy across multiple trials15

While Ketamine efficacy and safety are under caution, forthcoming ketamine research should continue to examine three major concerns: 1) elucidating ketamine’s mechanism of action; 2) understanding the administration profile necessary to provide a sustained therapeutic benefit; and 3) examining ketamine’s safety profile, particularly with repeated and likely low-dose administration. Knowing Ketamine can be a drug of abuse, it is difficult to argue its future as a potential drug to treat depression.

Blog written by Srini Natarajan

Nitrogen-Centered Radicals: A Forgotten Species?


In the late 1990s I was working on a chemistry project involving cascade reactions of C-centred radicals (CCRs). At that time, N-centered radicals (NCRs) were little used compared to their C-centered relatives and I was wondering if things had changed much since then.

Considering that the first example of the Hofmann-Löffler-Freytag reaction was reported in 18831 it seems that the development of the chemistry of NCRs has been fairly slow. More recently, in 2008, Zard2 described NCRs as a forgotten species with significant synthetic potential in a comprehensive review of intramolecular NCR cyclisation. NCRs have suffered from limitations because traditional methods for their generation have relied on the synthesis of N-X precursors and required harsh conditions for bond homolysis (Scheme 1, path A). New developments in metal catalysis (path B) and visible-light photocatalysis (path C) have resulted in greater use of NCR chemistry (for C-N bond formation) and advances in this field were reviewed by Zhang3 last year.

Micheal 1

 Scheme 13 Strategies in C-N bond formation based on NCR chemistry

Generation of NCRs using visible-light photocatalysis is particularly attractive due to low catalyst loading and mild conditions, with most reactions occurring at room temperature without the need for highly reactive radical initiators. This technology has been widely applied to radical amination chemistry in the last three years. An interesting example of this approach entitled ‘’Visible-Light-Mediated Generation of Nitrogen Centered Radicals: Transition Metal Free Hydroimination and Iminohydroxylation Cyclisation Reactions’’ was published by Leonori.4 One of the transformations described is a 5-exotrig cyclisation of iminyl radicals to give pyrrolines without the use of a transition metal catalyst (Scheme 2). A diverse range of oximes were converted to the corresponding pyrrolines, in good yields, and bicyclic heterocycles were also prepared using this methodology.

 

Micheal 2 

Scheme 24 Visible-light mediated hydroimination

The mechanism of this reaction involves single electron transfer (SET) reduction of the aryl oxime ether (A) by a visible-light exited photocatalyst (*PC), followed by N-O bond fragmentation to give iminyl radical (D) which can then cyclise onto the pendant alkene (Scheme 3). The role of cyclohexadiene (CHD) is to reduce the intermediate radical (E), followed by a second reduction of the photocatalyst (PC), which is then irradiated (PC®PC*) completing the catalytic cycle. Cyclic voltammetry studies suggested that that the key single electron transfer (SET) reduction, by excited state organic dye eosin Y, would only be efficient when using nitro-substituted aryl oxime ethers (1a-1d) with suitable reduction potentials. The 2,4-dinitro-aryl oxime (1a) was found to be the best substrate.

Micheal 3.png

Scheme 34 Proposed photoredox cycle and electrochemical studies. EY = eosin Y, ppy = 2-phenylpyridine

It was found that a different activation mode could be used to generate the iminyl radical without the presence of a photocatalyst (Scheme 4). When a solution of the aryl oxime ether (2a) and triethylamine in acetonitrile was irradiated with visible-light in the presence of CHD the previously observed hydroimination product (3a) was obtained, and also an unexpected iminoalcohol (4a). When CHD was not in the reaction mixture iminoalcohol (4a) was the main product. The mechanism proposed for this process involves formation of an unusual electron donor-acceptor complex (5) which undergoes SET giving the dipolar species (6). This species can then fragment, and undergo 5-exo-trig cyclisation to give radical (7). If the radical is not reduced by CHD it can be oxidised by attacking the nitro group (8) which after N-O bond homolysis, and hydrogen atom abstraction, gives the iminoalcohol (4a). Evidence for the source of the oxygen was provided by generation of 2-NO-4-NO2C6H3OH (10) from the reaction which was in contrast to 2,4-dinitrophenol that was produced from the original hydroimination.

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Scheme 44 Initial findings and proposed reaction mechanism for the iminohydroxylation

The chemistry of NCRs has been developing in recent years, but they still remain less well used than CCRs. Significant problems, such a functional group compatibility, need to be solved before they can become routinely used for C-N bond construction alongside traditional ionic chemistry. Visible-light photocatalysis seems very likely to play a role in future developments.

Blog written by Michael Annis

References:

1. J. L. Jeffrey and R. Sarpong, Chem. Sci., 2013, 4, 4092

2. S. Z. Zard, Chem. Soc. Rev., 2008, 37, 1603

3. T. Xiong and Q. Zhang, Chem. Soc. Rev., 2016, 45, 3069

4. J. Davies, S. G. Booth, S. Esaffi, R. A. W. Dryfe and D. Leonori, Angew. Chem. Int. Ed. 2015, 54, 14017

Chemical tools on trial: recent misleading information cases


For this week’s blog, I have picked it a still-hot and enjoyable Nature article by Monya Baker.1

How many times have you had screening results which make no sense to you end in frustration and unexplicable conclusions? How many times have you encountered that your chemical tools (hits) are neither as you thought, behaved oddly or even conducted regular quality controls on them and enough analytical tests? Read more to recognise unexpected setbacks.

The author goes through a few examples where researchers have encountered, for example, that chemical probes hitting specific targets suddenly became inactive when alternatives suppliers came onto stage. A futher realisation that one isomer was presented in different proportions if it was mixed with its other enantiomer (mirror-image like compounds sharing the same molecular formula) altering its activity leading to discover that sometimes, researchers do not know what they have in their hands if too much trust is put on commercial sources or the lack of further structural corroborations.2

When screening large compound libraries and identifying hits, the presence of false positives, impurities, degradation, mixed-up and messed-up stocks could also lead to infructouos crusades. Especially when liquid stocks are kept for months or years, at variable temperatures, the effect of poor solubility, side-reaction impurities, solvent effects and cockails of natural product mixtures amongst others. 3

Suggested online resources like: Chemical Probes Portal, Probe Miner and Probes and Drugs Portal 4 have been created to be used as a good first port of call toolbox with advice and information on which chemicals or drugs to use as well as public assessments.

The infamous case of BOSUTINIB, an approved cancer drug which was sold by nearly 20 suppliers with the chemical substituents wrongly located (please see ‘Spot the difference’ cartoon) has created havoc. jose

Both bosutinib and the other mis-identified isomer target cell-signalling proteins but with different potencies putting under trial numerous papers which reported data on the isomer of bosutinib rather on itself.5

Another researcher, Kim Janda caused an uproar when in its group they could not synthesise a molecule described to boost cell production of a powerful natural antitumor protein, TRAIL. The distributors had perpetuated the mistake in the original publication and after even clinical trials and patents were issued, he filled a patent with the proposed new active version of the TIC10 structure. 6

Another case emphasises how activity showed a big drop after small changes in contrast with bigger changes. Scientists realised that the present of Zn in their preparation was responsible for this activity without effect from the organic molecule whatsoever. Copper or Palladium from its use in catalytic reactions have been reported showing false positives.7

Even the present of NMP (N-methyl-2-pyrrolidone) a polar solvent used in some cases for keeping chemical probes in solution has recenlty showed anticancer activity in control tests, with potential implications in misleading the potency of the substances contained on it. 8

A list of common-sense leading practises to suppress these errors are given in the paper:

  • Use and buy chemicals by their CAS number (unique identification to chemical structures)
  • Request a detailed quality control certificate from external suppliers
  • Place enquires about the synthetic method used
  • Perform independent or in-house analysis upon receipt of the starting chemicals and reagents
  • Structural forms, chiral compounds, potential ambiguity in their chemistry substitution, then determine their optical purity and apply chiral chromatography techniques to isolate single forms.
  • If possible, previous in-house synthesis and determination with structural characterization.

Mismatching results, not-well documented suppliers, dubious chemical insertions (not well validated) as well as poor purities and the presence of contaminants (even at low concentrations) are always to blame for cases like those described in the article over the years. Albeit the final responsibility lies on the chemist’s team who need to be reassured by exploring and conducting further unequivocal tests.

The views represented in this blog are the author’s own.

Blog written by Jose Gascon

References:

  1. https://www.nature.com/nature/journal/v548/n7668/pdf/548485a.pdf
  2. Huber, K. V. M. Nature, 508, 222–227 (2014).
  3. Bisson, J. et al. J. Med. Chem. 59, 1671–1690 (2016)
  4. See: Chemical Probes Portal (www.chemicalprobes.org ), Probe Miner (www.probeminer.icr.ac.uk) and Drugs Portal (www.probes-drugs.org )
  5.  https://www.chemistryworld.com/news/pfizers-response-to-compound-fraud-spotlights-quality-issues-/9234.article
  6. https://phys.org/news/2014-05-chemists-cancer-drug-candidate.html ,Oncotarget, 2014, 5(24): 12728–12737 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350349/
  7. Hermann, J. C. et al. ACS Med. Chem. Lett. 4, 197–200 (2013)
  8.  Shortt, J. et al. Cell Rep. 7, 1009–1019 (2014).