The Ultimate Neurochemist's Bookshelf

[seep]

Assuming unlimited budget, what titles would this include? What titles must it include?

Also, which of the more comprehensive journals/periodicals should one subscribe to? (Aside from ultra-subspecialty-specific journals on, say, snail orgasms).

And as a side question, to what extent should one familiarize himself with physics? Mathematics? Computing?

 

[Hammilton]

the last bit is all dependent on what area you're interested in.

It's a wide field.

more and more biochem is being done on computers

 

[PsychedelicPeptide]

Depends on your interests. What kind of neurochemist do you want to be?

 

[shibireru]

Great topic.

I, personally, am very interested in rational drug design and synthesis. I also ought to develop a sense for what substances might be toxic, how a substance is apt to be metabolized by the body, and whether or not those metabolites be toxic or not. Any recommendations for me?

I don't mean to co-opt the thread here. Sorry. It's just that it seems it would be silly to start my own thread in order to ask a very similar question. Wasteful really. And annoying. Definitely annoying. Yeah. I'm trying to be less annoying, so, as if I were Pavlov's dog, you should reinforce this slightly less annoying behaviour with a reward.

 

[seep]

Depends on your interests. What kind of neurochemist do you want to be?

I have an obsession with the role of the CNS in mediating sexual desire.

Also the spectrum of autistic disorders.

Also, neurodegenerative syndromes.

Also, prenatal and infantile innervation in humans, as well as lifelong neural regeneration in certain organisms (especially cephalopods).

It's pretty hard to leave anything out. I'm technically an undergrad following a pre-med curriculum. But quantitative and qualitative analysis of neurochemical processes are especially fascinating now, as it seems the two fields are rapidly converging. If you get a chance to read chapters 2 thru 6 of:

http://www.cambridge.org/catalogue/catalogue.asp?isbn=9780521886086

there's a point where everything ceases being multiple integrals and partial differentials and becomes some kind of harmonious, multidimensional, polychromatic landscape.

 

[Jamshyd]

"Neurochemist"? You mean you want to study the chemical makeup of the nervous system? Get ready for delightful protein chains and ion channels!

 

[permastoned]

I've put my med degree on hold to study a bachelor of science (molecular and drug design). Maybe one day I can fulfill my dream of becoming a drug developer for a pharmaceutical company of some sort. Who knows. But the topic i find extremely interesting,

 

[PsychedelicPeptide]

Well... I got a chemistry BS, math minor, but took as much extra neuroscience and physics classes as I could (for "fun"). Started as "med school" major too but quit that idea after freshman GPA was 2.6. =) It's ok though I'd be a good doctor but probably am a better engineer.

Now I am trying to finish biochemistry PhD with strong emphasis on molecular design, in both my work but also spare time, most focus is on synthetic peptides.

I don't know if people here are looking for advice or what? I think there's a huge potential for work in proteins/peptides yet, especially for CNS targets. Less so for small molecules mainly because we have discovered so much already with them, and their utility is less than that of a peptide due to reduced size, but still it is an option of somewhere to specialize in. There's also work to be done potentially with more exotic things like polynucleotides, or other hybrid molecules with metals, polymers, conjugates, etc.

The point is though if you want to get into this kind of work the best thing to do would be to find a research lab or drug company to work in that does the kind of stuff you want to focus on. It is a bit hard to do if you are not familiar with any of the professors, I could sift through someone's university research staff homepage if they need help finding a lab to look for that does drug design-type work. Send a PM with a page to look at.

 

[permastoned]

Less so for small molecules mainly because we have discovered so much already with them, and their utility is less than that of a peptide due to reduced size

For just one example of the utility of small molecules, there are so many more receptors to be uncovered of which we could probably not even fathom the potential, many of which can be agonised by a small molecule. Just because you like peptides does not mean you have to devalue the little guys.

 

[Jamshyd]

^ That shows just how narrow-scoped your amphetamine-inflated head is, to be blunt about it...

What PP says is true. Research is turning away from monoamines because they have proven to be too "vague" to be of any good use in medicine.

Or at least, enlightened research.

There is still big money to be made by multinationals on the serotonin=happy market.

 

[sony123]

Well... I got a chemistry BS, math minor, but took as much extra neuroscience and physics classes as I could (for "fun"). Started as "med school" major too but quit that idea after freshman GPA was 2.6. =) It's ok though I'd be a good doctor but probably am a better engineer.

Now I am trying to finish biochemistry PhD with strong emphasis on molecular design, in both my work but also spare time, most focus is on synthetic peptides.

I don't know if people here are looking for advice or what? I think there's a huge potential for work in proteins/peptides yet, especially for CNS targets. Less so for small molecules mainly because we have discovered so much already with them, and their utility is less than that of a peptide due to reduced size, but still it is an option of somewhere to specialize in. There's also work to be done potentially with more exotic things like polynucleotides, or other hybrid molecules with metals, polymers, conjugates, etc.

The point is though if you want to get into this kind of work the best thing to do would be to find a research lab or drug company to work in that does the kind of stuff you want to focus on. It is a bit hard to do if you are not familiar with any of the professors, I could sift through someone's university research staff homepage if they need help finding a lab to look for that does drug design-type work. Send a PM with a page to look at.

i am a student that does work in a protein synthesis lab that sells there products to large pharm( Pfizer, Merck ect). just a warning, but many of the peptide chemists were laid off because production of peptides is becoming increasingly outsourced to countries like india, where they can be obtained cheaper.

i guess that really doesn't really matter if you are only interested in research

 

[DrGonzo899]

I think what the OP wanted was a list and explanation of some beginners books.

PIKAL and TIKAL anyone?

 

[permastoned]

^ That shows just how narrow-scoped your amphetamine-inflated head is, to be blunt about it...

What PP says is true. Research is turning away from monoamines because they have proven to be too "vague" to be of any good use in medicine.

Or at least, enlightened research.

There is still big money to be made by multinationals on the serotonin=happy market.

Who said that I was referring only to monoamines? That was your assumption, evidently your head has been a bit overinflated by amphetamines.

 

[vecktor]

^ no need to get personal.

peptides are pretty poor drugs as a general rule, unstable, poor bioavailability crap metabolism. pharma will keep on strugling with them because they are easy to make.
small molecule peptide mimetic drugs are where the smart money is.


books:
must include:
The Organic Chemistry of Drug Design.
Pihkal
Tihkal
Merck index.
Lednicers' series of books.

then the books that fit your speciality.

 

[permastoned]

^ I agree, there was no need to get personal, so I don't know why he decided to. I said nothing insulting in my original post. I also said nothing that indicated that I took amphetamines or that I am even interested in the monoamines (whether I may or may not be).

I am in concurrence with vector regarding the value of small molecule peptide mimetic drugs.

Additionally,

reduced size

can often be beneficial for a drug.

 

[PsychedelicPeptide]

Well if anyone should feel insulted, I think it would be me. =O

permastoned, do you really think there are that many undiscovered human receptors with potential to provide new aspects of euphoria or pleasure that we have yet to experience? I do not. We know the main small molecule neurotransmitters (5-HT, DA, NE) involved in pleasure/reward. To try and keep on topic here (see my 4th to last sentence) I can reference this brand new review article:

----------------------------------------------------------------------------------------------------------
Cell Mol Life Sci. 2009 Jun 12.
Depression and antidepressants: molecular and cellular aspects.
Lanni C, Govoni S, Lucchelli A, Boselli C.

Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Viale Taramelli 14, 27100, Pavia, Italy.

Clinical depression is viewed as a physical and psychic disease process having a neuropathological basis, although a clear understanding of its ethiopathology is still missing. The observation that depressive symptoms are influenced by pharmacological manipulation of monoamines led to the hypothesis that depression results from reduced availability or functional deficiency of monoaminergic transmitters in some cerebral regions. However, there are limitations to current monoamine theories related to mood disorders. Recently, a growing body of experimental data has showed that other classes of endogenous compounds, such as neuropeptides and amino acids, may play a significant role in the pathophysiology of affective disorders. With the development of neuroscience, neuronal networks and intracellular pathways have been identified and characterized, describing the existence of the interaction between monoamines and receptors in turn able to modulate the expression of intracellular proteins and neurotrophic factors, suggesting that depression/antidepressants may be intermingled with neurogenesis/neurodegenerative processes.
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Which talks about a few peptide receptors which are now being looked at as anti-depression targets. Will they yield anything useful? Well we don't really know yet because we don't have the best analogs to test the hypotheses. There is some good work done on CRF antagonists by Neurocrine Biosciences but that's about all I am aware of. All that is needed really is someone to design longer acting agonists or antagonists for whatever receptor with a preferred method of getting them into the brain, whether that be intranasal permeability, passive BBB transport, targeted delivery, etc is up to them to figure out.

There's also potential in attempting to "re-target" things like the serotonin system with newly designed modulators based on peptide/protein OR small molecule materials, specifically looking at modulating interactions in the pathway that perhaps we have yet to look at for whatever purpose you seek (euphoria, anti-depression, etc). However I again will side with peptides because their greater size and structural flexilibty permits greater access to playing novel roles in making NEW & NOVEL high affinity interactions take place in the brain.

There is a point where smaller molecules just cannot achieve what larger ones can. Reduced size also brings with it greater chances of off-target action (the biggest problem with small molecules). The true cut-off? Well lets put it this way:

To make a good "small molecule peptidomimetic" in the first place, you have to understand how the peptide itself works at the receptor. Hence if you don't have the right grounds, you will never even have a chance.

A good example is the failure of all glucagon receptor small molecule antagonists discovered to date, largely through library screening. Look up the papers, see the interest pharma obviously has/had in it, and count the failed attempts. So if you guys want to focus on organic synthesis, go ahead. But don't say I didn't warn you. ;-P

Also things like "instability, poor bioavailability & crap metabolism" are thoughts of the past. Solid phase synthesis and chemical modification have outgrown these concepts rather quickly. vektor I am confused what "pharma will keep on strugling with them because they are easy to make." is supposed to mean unless this is a jab at pharma? Either way peptide synthesis on kilogram scales is very, very doable for pretty much anything these days. For example look up conotoxin analogs for the use of pain (ziconotide specifically). It has multiple disulfides and the yields at large scale are <20%, yet this has not slowed the placement of the product onto the market. Synthesis is not a problem.

Pharma will make tons and tons of money off peptides because they will continue to license up university patented material and make the good shit that the research labs discover. The 80s and insulin/antibodies (genentech, lilly) ushered in the thought of a new era for pharma a bit prematurely, and I think they expected it all to happen at once versus a more slower development of high quality peptide-based therapeutics. Well the time is getting here and there are vast unmet therapeutic needs for CNS disorders, which peptides provide new ways of treating assuming we have "neurochemists" smart enough to get the jobs done right.

So to me, the ultimate neurochemist's bookshelf would probably be filled a lot more with paper print-outs, journals and conference proceedings as these contain the most up to date information, and if the neurochemist really wants to be on the ball then he probably won't have much time or use for "book style" reference materials beyond his undergraduate years. =)

Journals: Science, Nature, Nature Chemical Biology, Nature Biotechnology, Molecular Pharmacology, Cell, Nature Neuroscience, Nature Medicine, J Neuroscience, Bioorganic & Medicinal Chemistry Letters, Angewandte chemie, J Med Chem, JACS, PNAS, Neuropsychopharmacology, Peptide Science

I try to look at the publication lists for these sites every month or so. There's a few I'm missing I think but I just got a new computer and had to re-do my journals toolbar and lost all the old stuff I had listed. =/

 

[Hammilton]

Right, but peptides are still crap for drugs. You can't get around the issues of metabolism, bioavailability CNS penetration, etc, etc. Or rather, there are ways, but like Vecktor said, small molecule peptimimetic drugs are a far better option, and I don't see this changing in my lifetime. I don't see it changing in my sons lifetime either, though he's probably going to need to speak chinese. Oh crap he got the DVD I've been waiting so patiently on. Don't worry it's fine!

permastoned, do you really think there are that many undiscovered human receptors with potential to provide new aspects of euphoria or pleasure that we have yet to experience? I do not. We know the main small molecule neurotransmitters (5-HT, DA, NE) involved in pleasure/reward. To try and keep on topic here (see my 4th to last sentence) I can reference this brand new review article:

I think some euphoric receptors will be found. Who would have guessed that drugs binding to the α2δ subunit of the voltage-dependent calcium channel in the CNS would be euphoric? pregabalin is generally accepted as recreational, and gabapentin in some people (personally I like it, but not as much as pregabalin).

Or the GHB receptor?

Who knows, TAAR agonists may be recreational, too. Maybe CCK-A antagonists will be (doubtful, but I haven't seen anything about self administration of them.

There are quite likely CNS receptors that will be euphoric, but probably not in the way that existing drugs are.

 

[vecktor]

^^ my point was that pharma will continue making peptides because they are easy to synthesise.
my personal take on this is that small molecules will continue to dominate the pharmaceutical market, peptides have their place too but I think they will be minor players for the near future at least.

I look at the peptide receptors, like MOR or CCK both of which interest me, both of which show that having enough space for the peptide means that 'small' molecules can be taylored to fit with enough room for lead modification and optmisation. no peptide agent is ever going to compete with small molecule opioids. In the same way when a novel antidepressent is fully developed to exploit the CCK-B receptor, it is practically guaranteed that it will not be a peptide.

Most people I meet on the ground in pharma don't think peptides are the blockbusters of the future however they are chemists not biologists, however the morons that run pharma like the massively parallel, high throughput quantity not quality approach that peptides and peptide screening allow. it loks good to have massive numbers of lead peptides being churned out.

We still don't understand any of the monoamine GPCRs properly, at each turn the situation gets more complex with agonist directed trafficking, multiple downstream signalling, mutiple isoforms of the receptor, feedback variations in the receptor population and type etc etc. We don't understand the monamine transporters either. Poking around just the well known small ligand GPCRs is going to give new therapies and novel recreational drugs too... not to mention the number of orphan receptors which came from the human genome project, still much to be done.
even something like the CB1 receptor has different agonist dependent signalling, CB1 agonists with a different profile of effects will appear, and yes they will be small molecules, not peptides.

Put it this way I am not going to retrain to do peptide synthesis genetic engineering and protein expression.

 

[Jamshyd]

^ I agree, there was no need to get personal, so I don't know why he decided to. I said nothing insulting in my original post. I also said nothing that indicated that I took amphetamines or that I am even interested in the monoamines (whether I may or may not be).

Hey, I'm not the one making potentially harmful recommendations on a HR forum.

Nor am I the one who dick-sizes:

Yes.. I took 150mg of d-amp and 30 seleg and nothing. Time for permastoned to take a break from the phetty phetties. And his exams aren't even over! Poor poor permy.

What gets on my nerves is under-informed people pretending to be pharmacology-gurus (which is the attitude I perceived from your post here).

The fact remains that real "progress" is happening in research that has abandoned small things (like monoamine) and focuses on the bigger picture (like Hormones - again, just an example).

 

[Hammilton]

What gets on my nerves is under-informed people pretending to be pharmacology-gurus (which is the attitude I perceived from your post here).

I get on my nerves too.