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:
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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. =/
