The Ultimate Neurochemist's Bookshelf

[shibireru]

^ 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.

It seems to be your fancy to ascribe this way of thinking to just about everyone and usually without even so much as a hint of it being justified. I recall that you did the very same thing to me, though there was no indication that I thought this way, the last time there was a thread on book recommendations (or was it a thread of another topic entirely in which I merely asked for book recommendations and, as in this thread, received none because I am just too inferior to everyone here for them to deign to plop their hands down on to a keyboard and type the names of a few books? God, you people are arrogant cunts.)

Anyways, I almost never see you post, but when you happen to do so here in ADD, you're typically criticizing someone for having too much faith in the monoamine hypothesis of depression. We get it; that hypothesis has many shortcomings and failings. Give it a rest. Or at least be less pugnacious about it.

As for this exasperatingly idiotic argument, let's summarize it and bring it to an end by saying:

Small molecules = good, but limitations principally relating to low specificity
Peptides = higher specificity and able to activate certain receptors which small molecules can not, but probably more significant and more intractable limitations
Each is more useful than the other in certain domains.


Now, perhaps someone here can take his criticisms of me to heart and keep his comments topically relevant by actually giving some recommendations to seep, the, you know, topic of this thread. I don't suppose that would take nearly as much energy as this petty brain-dead arguing has.

 

[Hammilton]

higher specificity and able to activate certain receptors which small molecules can not, but probably more significant and more intractable limitations

nonsense.

I do not believe there will be many receptors that a small molecule cannot be made to agonise or antagonise

 

[shibireru]

nonsense.

I do not believe there will be many receptors that a small molecule cannot be made to agonise or antagonise

That's not really the point. The point was that this was a stupid, off-topic argument that you're apparently trying to draw me into.

Oh, well, what the hell. What about the oxytocin, orexin, and human growth hormone receptors? Aren't those just a bit large... er something?

 

[PsychedelicPeptide]

I thought my last post had tons of great information for a young neurochemist-to-be.

But we need to take Hammilton's words very closely. He says "I do not believe there will be many".

So before I say anything else, Hammilton could you provide us with your definition of what many constitutes in this sense? A percentage would be nice.

 

[Hammilton]

That was the point? this is a topic that does merit discussion, but you're right, this isn't really the place. In the end, at this point, it's all speculation though, but history suggestions that small molecules will continue to dominate for a long long time.

These are some of the books I have on hand, though I did not get them first hand.

http://www.amazon.com/Biochemical-B...=sr_1_2?ie=UTF8&s=books&qid=1246389919&sr=1-2

http://www.amazon.com/Handbook-Cont...=sr_1_4?ie=UTF8&s=books&qid=1246389919&sr=1-4 (Shope around for this one. Some sell it for more than Amazon asks even. I got mine for just under 100, and I see there's one used for 75 bucks right now, which is a huge steal assuming it's in good condition- but given the length it's been out, it can't be THAT bad).

http://www.amazon.com/Molecular-Reg...r_1_12?ie=UTF8&s=books&qid=1246389919&sr=1-12

http://www.amazon.com/Organic-Chemi...sr_1_2?ie=UTF8&s=books&qid=1246390570&sr=1-2#

These are the ones I have that I liked. There are almost certainly better books out there, perhaps for less, but I found these to be useful.

Seriously if you trawl amazon.com you'll find tons of great utility.

 

[Hammilton]

I thought my last post had tons of great information for a young neurochemist-to-be.

But we need to take Hammilton's words very closely. He says "I do not believe there will be many".

So before I say anything else, Hammilton could you provide us with your definition of what many constitutes in this sense? A percentage would be nice.

Oh certainly, that was a great post.

I would think >25% is most likely, 15-25% on the high side. Right now we're talking less than 1% right? Even if things go really well in the next 40 years, I think that's a best chance sort of thing.

Advances in CNS administration and penetration and halflife / metabolism could well make that way low though. The low cost means they will be heavily investigated and every possible chance given.

 

[permastoned]

Why must some of you be so hasty to make assumptions??!

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.

Firstly, I did not at any stage within my post state that I was interested only in the modulation of pleasure or euphoria. Once again, that was your assumption. Secondly, yes, let us assume that I was referring to the modulation of pleasure. "We know the small main molecule NTs involved in pleasure and reward... "

But wait, we are only just beginning to understand the downstream effects of activation of any of the SUBTYPES of these receptors. The variability of effects that have been noted from even subtleties such as activation of the 5ht2a causing dopamine release and the 5ht2c causing gaba release, lead to far more many new options for drugs than one may think. Supposedly antagonism of the 5ht7a is anxiolytic and antidepressive!

So you can have an agonist, antagonist, or inverse agonist of any of these receptor subtypes... and you can have a mixture of them to achieve an acquired effect.. and you think that the best drugs modulating these systems have been discovered yet? Think again, friend.

Continuing along the line of your assumption, delta opioid agonists have been shown to be potent antidepressives. H3 Antagonists have shown promise in the treatment of depression and a wide other range of diseases. And what about all the receptors that we have not yet discovered? Let alone, as Hammilton says, the alpha 2 sigma subunit of the voltage gated ca2+ channel or the GHB receptors, not even the receptor groups that we know about have been properly explored or exploited yet! And it is so arrogant for you to think that more that modulate pleasure or euphoria will not be found. And yes, a small molecule will be able to agonise/antagonise/inversely agonise this receptor. With regards to specificity, there are many specific small molecule drugs. Down to the pointt that we have drugs such as RS-102,221 "potent and selective antagonist at the serotonin 5-HT2C receptor, with around 100x selectivity over the closely related 5-HT2A and 5-HT2B receptors.'

Now combine this information with the fact that I am referring not only to the modulation of pleasure and euphoria, but to the modulation of any function of the CNS or PNS. Satiation of appetite, urinary incontinence, insomnia, etc. There are MANY.. that is right.. MANY undiscovered receptors to be exploited.. and we haven't even exploited those that we have discovered yet!!

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.

No shit that the activation of a monoamine receptor in turn causes downstream effects within the target cell such as varsious protein expression, BDNF release, neurogenesis, etc... That is generally what the idea of activation of a GPCR is.. your article does not give your cause huge support. Instead it attempts to be a rather vague review of the mechanism of the involvements of peptides following activation of receptors...

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.

Again, I never at any stage implied that peptide research was not necessary in order for effective small molecules to be developed. All that I originally said was that small molecules have not lost their role of being stars of the pharmaceutical industry, and neither will they for rather long time in my opinion.

Nor am I the one who dick-sizes:

Quote:
Originally Posted by permastoned View Post
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.

Sir, you are mistaken. Firstly, the quote you post is from an entirely different thread, which was completely unrelated to this one. Secondly, what you mistook for 'dick-sizing' was in fact a desperate cry for help. If I were to dick size, it would look like this:

7.3 inches

Oh, well, what the hell. What about the oxytocin, orexin, and human growth hormone receptors? Aren't those just a bit large... er something?

Yo' mumma just a bit large... er something...

 

[Jamshyd]

It seems to be your fancy to ascribe this way of thinking to just about everyone and usually without even so much as a hint of it being justified. I recall that you did the very same thing to me, though there was no indication that I thought this way, the last time there was a thread on book recommendations (or was it a thread of another topic entirely in which I merely asked for book recommendations and, as in this thread, received none because I am just too inferior to everyone here for them to deign to plop their hands down on to a keyboard and type the names of a few books? God, you people are arrogant cunts.)

Anyways, I almost never see you post, but when you happen to do so here in ADD, you're typically criticizing someone for having too much faith in the monoamine hypothesis of depression. We get it; that hypothesis has many shortcomings and failings. Give it a rest. Or at least be less pugnacious about it.

As for this exasperatingly idiotic argument, let's summarize it and bring it to an end by saying:

Small molecules = good, but limitations principally relating to low specificity
Peptides = higher specificity and able to activate certain receptors which small molecules can not, but probably more significant and more intractable limitations
Each is more useful than the other in certain domains.


Now, perhaps someone here can take his criticisms of me to heart and keep his comments topically relevant by actually giving some recommendations to seep, the, you know, topic of this thread. I don't suppose that would take nearly as much energy as this petty brain-dead arguing has.

LMAO, what the fuck are you smoking?

EDIT: Oh, and FYI, I just did a search (just out of curiosity since you bring it up), and I have 376 posts in ADD. That happens to be more than all your posts on all of BL. I find this a bit amusing .

 

[permastoned]

LMAO, what the fuck are you smoking?

You should know.. he doesn't blaze up..

He takes benzos/opes/stims, then posts lengthy amusing rants in an exuberant lexicon!

 

[PsychedelicPeptide]

I would think >25% is most likely, 15-25% on the high side. Right now we're talking less than 1% right? Even if things go really well in the next 40 years, I think that's a best chance sort of thing.

I am kind of confused by that. 25% of all protein-made receptors with either a small molecule or peptide/protein ligand will never have a small molecule agonist or antagonist then?

Heh, we could argue all day about these numbers and their significance.

To the question about the growth hormone receptor, and other tyrosine kinases like the insulin receptor superfamily (insulin, IGF-1/2, relaxins) and prolactin receptor, yeah their ligands are so huge I don't see a small molecule agonist/antagonist ever coming to light. These receptors have to dimerize to elicit signaling and although the receptor activation mechanisms in terms of ligand binding are still very unclear, I highly doubt a small molecule can take their place. They just have too many essential residues (especially aromatics) in exact locations spread throughout the molecules that are all known to be important for binding & activation. I'd consider these pretty much off limits to small molecules.

That's not to say I wouldn't like to see it happen though. As a diabetic on insulin, sure it would be nice to have a fast-acting tablet I can dissolve in my mouth or something instead of a needle, but I just don't see it working.

For stuff like the oxytocin receptor it's much more realistic as the peptide ligand itself is much smaller. Hell oxytocin is only 8 amino acids and is disulfide bonded into a circular structure at that, so it's pretty small to begin with. So the biggest hurdle there is just finding where on the receptor you want to target, knowing what conformation it will trap the receptor in, and making the molecule that does it well. Of course that's all easier said than done, but there's at least a few patents for oxytocin antagonists that pharm companies have come up with. Whether or not they are sufficiently potent and selective enough to be used for anything besides in vitro studies is the next question...

In the end, a neurochemist should be familiar with it all. Kids these days just have to know so much to be good at science. =)

 

[seep]

This may be tangential to the debates over whether or not the possibilities for developing novel psychoactive compounds are waning or expanding, but the ratio of discovered to undiscovered receptors and receptor subtypes (we can quantify this?) is not the only parameter here. You can't ignore how incompletely understood the synapse (in a generalized sense) remains. The same [incompleteness] obstacle applies to any given compound's mechanism of action at a given activity site (which is more than just the inverse of synapse activity). I'm generalizing enormously, but I wouldn't be surprised if this century's greatest contribution to neuroscience is some kind of biological analogue to Godel's incompleteness theorem--i.e. a FORMAL PROOF that the system itself can never be completely understood because of the irrefutable lack (which needs to be proven) of any independent variable (Godel would slap me for over-simplification).

And pragmatically speaking: pharm companies (and so much published research) are primarily driven by revenue potential, not munificence. I'm not just regurgitating opinion-page headlines: many of the researchers I know are conducting studies that completely shirk the scientific method. My friends who work for a pharmaceutical company that's part the DOW 30 are busy developing and testing drugs specifically marketed to compete with existing popular drugs (often their own drugs, about to go off-patent, which casts the researchers in the schizoid role of arguing against themselves--which is itself a parody of the scientific method). My point being that the big pharm firms usually care very little about the needs of humanity: and by extension, think about how catastrophic it is for an enterprising but small pharmaceutical corp to have the FDA disapprove their signature product (which may nevertheless be a fantastic compound w/r/t efficacy [amineptine? Though Servier is by no means an upstart].

Plus all the added complexity that is sure to come after geneticists' wrenches earnestly begin to work on human embryos, so that at some point (soon?) the phrase "human CNS" will beginm to lose meaning.

All of which makes me glad I'm at the foot of the stairs right now. In 1906 Golgi shared the Nobel prize in Medicine with the spaniard Ramon y Cajal: it's interesting to read their Nobel Lectures as they pretty much rip holes into one another (reticular versus neuronal hypotheses), in much the same way the debate proceeds here. Golgi, pompous and ultra-confident, turns out to be dead wrong:

http://nobelprize.org/nobel_prizes/medicine/laureates/1906/index.html


Thanks for the recommendations. MCAT in 2 months!

 

[permastoned]

This may be tangential to the debates over whether or not the possibilities for developing novel psychoactive compounds are waning or expanding, but the ratio of discovered to undiscovered receptors and receptor subtypes (we can quantify this?) is not the only parameter here.

Obviously it can not be quantified, however I would say that it is arrogant to assume that it would be in our favour at a stage when such rapid developments of new techniques and projects e.g. human gemone have only just developed, that are allowing the discovery of many more currently alien receptor families.

You can't ignore how incompletely understood the synapse (in a generalized sense) remains. The same [incompleteness] obstacle applies to any given compound's mechanism of action at a given activity site (which is more than just the inverse of synapse activity).

I don't really see how the mechanism of the synapse is SO relevant to drug composition. Considering it actually is fairly well understood. Sure, in some instances it will influence what kind of drug/what binding site it attaches to/what it agonises/what it inhibits/what it transcribes (and u get the point), but rarely in my opinion.

And pragmatically speaking: pharm companies (and so much published research) are primarily driven by revenue potential, not munificence.

HOMG are you serious?! I thought that Pfizer actually did it for their love of cuddwy bunny rabbits! Holy shit batman!

busy developing and testing drugs specifically marketed to compete with existing popular drugs (often their own drugs, about to go off-patent, which casts the researchers in the schizoid role of arguing against themselves--which is itself a parody of the scientific method).

In a very metaphorical way yes. In practice, they know what they are making, and the reason for which they are making. They realise that they are simply aiming to make a small modification to the drug in order to apply for a new patent. This could take all of a day in some instances, although it would be planned substantially ahead. In fact it is a realistic possibility that many of the drugs that come out today were known about 20 years ago even, but kept as secrets for the sake of staggered patenting.

think about how catastrophic it is for an enterprising but small pharmaceutical corp to have the FDA disapprove their signature product (which may nevertheless be a fantastic compound w/r/t efficacy [amineptine? Though Servier is by no means an upstart].

It seems pretty obvious to me that a potent dopamine reuptake inhibitor should not be thrown around like candy...

Thanks for the recommendations. MCAT in 2 months!

Good luck!

 

[samb834]

Im almost in my final year of my PhD in psychopharmacology and have found this book pretty handy at times...

http://www.amazon.co.uk/Principles-Neuropsychopharmacology-Robert-S-Feldman/dp/0878931759

Covers a large chunk of the topic and is fairly easy to get your head around, if thats your field/interest

Journals that I find pretty useful are Behavioural Brain Research, Psychopharmacology, Neuropsychopharmacology etc...

 

[morphiquet]

LMAO, what the fuck are you smoking?

EDIT: Oh, and FYI, I just did a search (just out of curiosity since you bring it up), and I have 376 posts in ADD. That happens to be more than all your posts on all of BL. I find this a bit amusing .

jamshyd, if all of your 376 posts here are that unqualified and dispensable like this^ one, then you're really the master %)

or maybe, you just got something wrong about the terms "small molecule" and "monoamine", which do not equal in any sense.
i guess you know what "monoamine" means, so let me explain to you what "small molecule" means.
they are, in general, molecules which are metabolically stable (in contrast to nearly all peptides), are small in size i.e. molecular weight and their targets principally include ALL biomolecules in a living organism, e.g. peptide receptors, enzymes, ion channels etc., and of course, also monoamine receptors/transporters.

i hope you even read my post before you blast me with your 377th post

 

[permastoned]

^ burned.

 

[jspun]

I find that Goodman and Gilman Guide to Pharmacological Therapeuitics to be an indispensible text (atleast the chapters pertaining to neuropharmacology).