Archive for the 'Neuropharmacology' category

On discovering new medicines

ResearchBlogging.orgA link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were "first in class", i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 "follower" drugs.

The review also focused mostly on small molecule drugs instead of "biologics" because of an assumption that the latter are all exclusively "target based" discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That's my formulation of what the authors term "target based screening" (which may include "molecular mechanism of action") discovery and "phenotypic screening" type of discovery. As they put it:

The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.

A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.

You will note that this is related to some comments I made previously about mouse models of depression.

The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:

For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome

and for target based approaches:

A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir

The authors even ventured to distinguish discovery approaches by disease area:

Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases

Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.

Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.

The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can't really go into the details but there are areas where my professional career is...affected, let us say...by the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:

at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.

Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.

in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.

Ultimately I think this review argues quite effectively for an "all hands on deck" approach to drug discovery but it can't help but come off as a strong caution to the folks that think that "smarter" (aka, "rational drug design") is the only solution. Yes, this points the finger at Francis Collins' big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
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Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480

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David Nichols on the impact of his scientific work with recreational drug users

Professor David E. Nichols is a legend for scientists who are interested in the behavioral pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, aka, 'Ecstasy'). If you look carefully at many of the earlier papers (and some not-so-early) you will see that people obtained their research supply of this drug from him. As well as much of their background knowledge from publications he has co-authored. He has also worked on a number of other compounds which manipulate dopaminergic and/or serotonergic neurotransmission, some of which are of great interest to those in the recreational user community who seek (ever and anon) new highs, particularly ones that might be similar to their favorite illicit drugs but that may not currently be controlled. Those who are interested in making money supplying the recreational consumer population are particularly interested in the latter, of course.

Professor Nichols has published a recent viewpoint in Nature in which he muses on the uses to which some of his work has been put:

A few weeks ago, a colleague sent me a link to an article in the Wall Street Journal. It described a "laboratory-adept European entrepreneur" and his chief chemist, who were mining the scientific literature to find ideas for new designer drugs — dubbed legal highs. I was particularly disturbed to see my name in the article, and that I had "been especially valuable" to their cause. I subsequently received e-mails saying I should stop my research, and that I was an embarrassment to my university.

I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people.

As with most scientists, I have little doubt. And ultimately, I agree with his observation that

There really is no way to change the way we publish things, although in one case we did decide not to study or publish on a molecule we knew to be very toxic. I guess you could call that self-censure. Although some of my results have been, shall we say, abused, one cannot know where research ultimately will lead. I strive to find positive things, and when my research is used for negative ends it upsets me.

It is unfortunate that Professor Nichols has been put in this position. Undoubtedly John Huffman of JWH-018 fame (one of the more popular synthetic full-agonist cannabinoids sprayed on herbal incense products) feels much the same about his own work. But I suppose this is the risk that is run with many lines of basic and pre-clinical work. Not just recreational drug use but even therapeutic use- after all off-label prescribing has to start somewhere. And individual health (or do I mean "health") practices such as high-dosing on blueberries or cranberries, various so-called "nutritional supplements", avoiding certain foods, exercise regimes, diets, etc may be based on no more than a single scientific paper, right?

So we should all feel some bit of Professor Nichols' pain, even if our own work hasn't been mis-used or over-interpreted...yet.

UPDATE: Thoughts from David Kroll over at the cenblog home of Terra Sigillata.

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Repost: The Women of MDMA Research

There is a #womeninscience meme bouncing around the Twitts today. Click the link and you'll see some of the conversation, even if you are not a habitual Twitter user. Please consider joining in with an observation about, well, anything related to the life of women in science. On the Twitts, on your blog, Facebook or in the comments here or elsewhere.

I have an older post that I wrote some time ago to introduce some of the women who have contributed to the science that I talk about on the blog. This post originally appeared 24 Jul 2008.


A comment left by a reader some time ago took exception to one of my posts highlighting another blogger.

wow, that is some excellent PR for a grad student to get for free. perhaps you could spotlight a female grad student as well...?

The ensuing discussion planted the idea for this post. Continue Reading »

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MDMA for PTSD: The first peer-reviewed clinical trial report

Jul 23 2010 Published by under MDMA, Neuropharmacology

ecstasypills.jpgMy readers will recall that I have blogged now and again about ongoing efforts to get 3,4-methylenedioxymethamphetamine (MDMA), the psychoactive compound preferentially sought as Ecstasy in recreational users, approved as a medication to be used in psychotherapy. The initial attempts have focused on the treatment of Post-Traumatic Stress Disorder. PTSD is a seriously debilitating condition and we may not have sufficient resources and knowledge to deal with, e.g., an anticipated uptick due to the current wars that the US is prosecuting.
I introduced the MDMA/PTSD Phase I clinical trials here, noting

The short version of the theory is that the subjective properties of MDMA (empathic, inhibition lowering, etc) are consistent with helping people in difficult psychotherapeutic situations (such as for post-traumatic stress disorder (PTSD) and, supposedly, end stage cancer anxiety) make therapeutic breakthroughs during a limited number of treatment sessions of talk therapy. This is not proposed as a chronic medication like a selective serotonin reuptake inhibitor (SSRI). The funny thing is, I approve of the concept of moving forward with clinical trials based on the available evidence.
Why not? I mean PTSD can be a very devastating psychological issue and if there are treatment-resistant cases that can benefit from a limited number of MDMA exposures, great.

I concluded that particular post with this observation.

As is general practice in medicine, sometimes there are going to be risks associated with therapy. Sometimes quite substantial risks can be acceptable if the alternative is bad. However we get ourselves into a world of trouble, sometimes even losing a perfectly helpful medication, if we are not as honest as possible, up front, over the actual risks.

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28 responses so far

Quackery adopting the ResearchBlogging iconography?

Jul 22 2010 Published by under #FWDAOTI, Neuropharmacology, Quackery

A Twitt from Dirk Hanson, of the Addiction Inbox blog, pointed to the Mini Chill drink which purports to be:

..the world's only drink guaranteed to make you feel great! Our all natural blend of herbs and aminos is Dr. formulated and proven to promote relaxation, improve mental focus and even boost your mood!

Dirk made some crack about this being an alcohol enhancer and, fascinatingly, the website for this product has a whole page for cocktail recipes. Mood enhancing, healthy...and a mixer! Oh joy...
MiniChillFACTS.pngAt any rate, I was searching for the Quack Miranda Warning when I clicked on the "Lab" page and I immediately noticed something funny. An icon right in the middle of the page is linked to the ingredients page which says the product contains:

four primary ingredients found in nature, all of which have been subjected to molecular research and clinical studies. These components are Valerian Root, Aminobutyric acid (GABA), Theanine and 5-HTP.

Oh this is a classic of misdirection and insinuation isn't it? "Molecular research" and "clinical studies" eh? Yet I bet not one single clinical study showing that this product has the benefits that they claim. Just guessin there. Anyway I'd best leave the quack busting to the real experts like PalMD and Abel Pharmboy, so let's return to the iconography.
ResearchBlogging.orgThat icon, linked to their supposed evidence mind you, reminded me of this ResearchBlogging.org icon. When you put them together like this it is obvious that the Mini Chill icon is not an exact duplicate. But still. It evokes the ResearchBlogging icon, does it not? Surely this is not just me?
If you will recall the ResearchBlogging icon is the descendant of a prior icon. The goal of this icon was, of course, to evoke rapid identification with the intent of ResearchBlogging.org itself. I.e., to form a sort of Good Housekeeping seal of approval that the post you were reading met certain basic standards.
If this is not simply a coincidence, I find it really interesting that some quack product would try to coopt the authority of ResearchBlogging.org. Among other things it would seem that marketing donks think that the ResearchBlogging.org is actually meaningful to people. That's good at least.
I never did find the Quack Miranda Warning.

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The Third Reviewer is....you!

I have occasionally mentioned that I really like the way that Nature Publishing Group (NPG) have promoted the online discussion of scientific research articles. After all, the publication of an article is merely the starting point and the authors' interpretations of their data are only part of a larger set. Science proceeds best when we collaborate with our data, our ideas, our interpretations and our conclusions. Internet technologies can assist with this process. Indeed, these technologies already are assisting and have been doing so for some time. How many times in the last month have you used email to discuss a figure or a paper with a colleague? A ubiquitous phenomenon, is it not? Yeah, well when I started graduate school there was no email*.
I have also, I confess, waxed slightly critical of the execution of online paper discussion. Although I mostly bash NPG because they leave so much tasty chum lying in the water, I am generally critical; PLoS hasn't really managed to do much better than the NPG titles when it comes to consistent online discussion.
Science blogs are slightly better at generating robust discussion of an article which in some cases feels a little more like journal club. This latter is a touchstone target for this behavior, IMNSHO. Science blogs suffer, however, from a lack of focus and a lack of comprehensive coverage. Researchblogging.org is a focal portal to select the journal article discussions out from the cacophony of a typical blog but again, it tends to suffer from coverage issues. The audience is presumed to be a general audience by most science bloggers and therefore they tend to select topics of general interest.
This brings me to a new internet creation: The Third Reviewer

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16 responses so far

Docs, you need to take more time 'splaining ADHD meds to parents

May 25 2010 Published by under Drug Abuse Science, Neuropharmacology, Parenthood

As you know, DearReader, I enjoy talking about science with the Boss, aka the US taxpayer, aka my friends, neighbors and acquaintances. In fact I not only enjoy it but I think of it as responsibility both to them, the people who fund the NIH, and to my fellow scientists.
You are also likely aware that I have school-aged children and therefore this circle of interactions with the taxpayer includes chatting with the parents of children that my own kids interact with.
One of the conversations that arises fairly frequently has to do with medications prescribed for Attention Deficit Disorder / Attention Deficit Hyperactivity Disorder (ADD, ADHD). This is, of course, a big can of worms to be opening on the blogosphere and let me make it clear I'm not planning on discussing ADHD science per se.
In brief outline of the issues let us reflect on the following.
-as with most of the mental/behavioral disorders there exists a distribution or spectrum of traits, symptoms or behaviors. Depending on how you want to view them. At some point of extremity, we (meaning the clinical psychiatry/psychology communities) define or diagnose conditions as pathological and in need of intervention
-diagnosis is imperfect, we do not have alternate biomarker validation in most cases and there will always be those on the threshold
-specific traits or behaviors can be either trivial or maladaptive depending on circumstances.
-therapeutic intervention, even in the clearly pathological cases, is less than 100% successful.
-interventions which involve repeated or chronic administration of drugs which affect brain and other body systems have risks.
These end up being complicated situations for parents to navigate. Parents are subject to the usual stigmas about mental health, and are reluctant to consider that their child might actually benefit from therapeutic drugs. They are worried about the lasting consequences. They have, perhaps, run across the criticisms (some valid, many not) of ADHD diagnosis and medication that are available on the internet.
And their doctors are failing them.

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60 responses so far

doin it right

[ Please welcome our guest blogger, who identifies as robin, just your average everyday neuropharmacologist. -DM ]
One of the most important yet overlooked tasks of the average pharmacologist is dissolving drugs into solution. Those of you who work with things that don't have to cross the blood-brain barrier probably have a generally easier time dissolving shit than those of us who prefer to study CNS-active compounds. For those of us who play with compounds that are hydrophobic enough to cross the blood-brain barrier, I can testify that those range from fairly easy to major suck to put into an aqueous solution.

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14 responses so far

Discriminating Cathinone Analogs

Mar 15 2010 Published by under Cathinone, Drug Abuse Science, Neuropharmacology

4-MMC.jpg
source
My Google news alert for MDMA, Ecstasy and the like has been turning up references to a cathinone analog called variously 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT and a few other things. There has been one fatality attributed* to 4-MMC that I can find and a few bits of seized-drug analysis confirming that the stuff is indeed being used. A quick scan over at PubMed finds little reported on the effects of this compound in animal models or in humans. I did, however, run across an article on other cathinone analog drugs that caught my attention.
ResearchBlogging.orgThe newpaper reports on 4-MMC coming out of the UK, for the most part, are experiencing the usual difficulty in characterizing the subjective properties of an analog of a stimulant class of drugs. This not dissimilar to the case of MDMA and relatives such as MDA, MDEA/MDE which are structurally similar to amphetamine and methamphetamine but convey subtly different subjective properties. This also gives me an opportunity to talk about an animal model used quite a bit in drug abuse studies: The drug-discrimination assay. The paper of interest is the following one.
Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Dal Cason TA, Young R, Glennon RA. Pharmacol Biochem Behav. 1997 Dec;58(4):1109-16. (DOI)

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Dr. leigh on the pharmacology of marijuana

HAHAHAHAHAHHAHHA! Okay dope fans....go beat up on the new doc in town for awhile....

CB1 receptors affect the function of the presynaptic terminal. When CB1 receptors are activated, they signal through G proteins to close calcium channels, preventing entry of calcium into the terminal. Calcium is needed for vesicles to fuse with the membrane and release inhibitory neurotransmitters into the synapse. So CB1 signaling stops inhibitory neurotransmitters from being released to the postsynaptic neuron. CB1 receptor activation also results in opening of potassium channels. In a resting neuron, these channels are closed. Outflow of positively charged potassium ions leads to increases in the net negative charge across the membrane. This is called hyperpolarization, the opposite of depolarization. As you might imagine, since depolarization causes neurons to fire, hyperpolarization keeps a neuron from firing. This further decreases the chances that neurotransmitter will be released from the presynaptic terminal. There are some other effects too, which I won't detail here.

Now let us see, do you think this closing bit is a tad optimistic?

I hope that this helps to make the effects of marijuana make more sense. For the record, I am not interested in discussing policy or the legal status of the drug. I am just here writing about how it works.

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