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The Neuroscience behind the 5-HT2a receptors.

MedicinalUser247

MedicinalUser247

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The 5-HT2a receptor is a subtype of the 5-HT2 receptor and is a G-protein-coupled receptor. The 5-HT2a receptor is a cell surface receptor. This receptor was first noted for it's importance as a target of serotonergic Psychedelic drugs such as L.S.D., psilocybin and later on M.D.M.A. Low serotonin levels are seen in depression which lead to the development of S.S.R.I.s. The 5-HT2a receptor is mainly to couple to the G.a.q signal transduction pathway. With receptor stimulation with agonists G.a.q and B-y subunits dissociate to initiate downstream effector pathways. G.a.q stimulates phospholipase C activity which subsequently promotes the release of diacylglycerol and inositol triphosphate which in turn stimulates protein kinase C activity along with the release of calcium ions. This reveals some of the mystery behind the 5-HT2a receptors. It's one of the reasons drugs such as L.S.D., psilocybin, tryptamines and M.D.M.A. work. And if we didn't have the 5-HT2a receptors in are brain than none of these substances would work. We would be completely immune. The study of these receptors are important especially in the field of drug design. And it's my opinion that everything related to the 5-HT2a receptors should be further studied. What are your thoughts on this ?
 
Intracellular 5ht2a receptors have been proposed to mediate many of the effects of psychadelics.
https://pubmed.ncbi.nlm.nih.gov/36795823/

Bryan Roth is a good name to look for on papers if you are interested in the serotonin receptor. He has gotten a lot of crystal structures with it bound to different compounds, and uses that data to really break down the shape of its binding pocket, and specific molecular contacts that make a drug an agonist or antagonist, or control whether the receptor signals with G proteins or through beta arrestin.

He just dropped a paper about using alphafold 2 to dock compounds to the 5ht2a receptor and the sigma 2 receptors. This paper illustrates how drug discovery occurs today: a target is identified, and then compounds from a library of millions will be computationally screened, and then the hits will be physically screened to find things that work, and the structures may get modified to fix functional issues (poor bioavailability, quick or overly slow metabolism, off target toxicity...). Only then does the drug get sent into trials.

https://www.biorxiv.org/content/10.1101/2023.12.20.572662v1.full (this is just the preprint, but it's free).
 
In chemistry, Orbital theory is a way of describing the electronic structure of molecules using quantum mechanics. In orbital theory electrons in a molecule are not assigned to individual chemical bonds between atoms, but are used as moving under the influence of the atomic nuclei in the whole molecule. Quantum mechanics describes the spacial and energetic properties of electrons as molecular orbitals that surround two or more atoms in a molecule and contain valence electrons between atoms. Orbital theory revolutionized the study of chemical bonding by approximating the states of bonded electrons, "orbitals", as linear combinations of atomic orbitals. These approximations are made by applying the density functional theory or "Hart-Fock" models to the Schrodinger equation. Orbital theory and valence bond theory are the functional theories of quantum chemistry. With orbital theory people can apply this chemistry to create new molecules. Such as new drugs or new chemicals. It comes down to what your looking to use orbital theory for. What are your thoughts on this ?
 
I'm going to talk a little bit about Biochemistry. Biochemistry is the study of chemical processes in related living organisms. It's a mix of both biology and chemistry. Biochemistry is usually dived into three groups. Structural biology, enzymology and metabolism. Biochemist basically focuse on understanding the chemical basis which allows biological molecules to give rise to the processes that happen within living cells and between cells. Basically relating greatly to the understanding of tissues and organs an also the organisms structure and function. Most biochemistry deals with the structures, bonding, functions and interactions of biological macromolecules. Such as proteins, nucleic acids, carbohydrates and lipids. They look at the structure of cells and thier function in life. The chemistry of the cell also depends on the reactions of small molecules and ions. These can be inorganic or organic. The mechanisms used by cells to harness energy from the environment as in chemical reactions are know as metabolism. The stuff found in biochemistry are applied primarily in medicine, nutrition and agriculture. In medicine biochemistry investigates the causes and cures for diseases. Nutrition studies how to maintain health and wellness plus the effects of nutritional deficiencies. With agriculture biochemist investigate soil and fertilizers. With the goal of improving crop cultivation and pest control. In recent years biochemical methods have been combined with a problem solving approach from engineering to manipulate living systems in order to produce useful tools for research, industrial processes and diseases. With biochemistry it makes modern life more livable. What are your thoughts on this ?
 
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Dopamines chemical structure is 3,4-Dihydroxyphenethylamine. There are 5 types of dopamine receptors in the brain. D1,D2,D3,D4 and D5. Dopamine receptors are a class of G protein coupled receptors that are prominent in the vertebrates central nervous system. Dopamine receptors activate different effectors through not only G protein coupling, but also signaling through different protein interactions. Well, dopamine receptor interacting proteins anyway. The neurotransmitter dopamine is the primary endogenous ligand for the dopamine receptors. Dopamine receptors are implicated in many neurological processes, including motivational and incentive salience, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. So, the dopamine receptors are common neurologic drug targets. Such as drugs like cocaine, methamphetamine and designer drugs. And if we didn't have dopamine and dopamine receptors we would be completely immune to these substances. Plus we would be more like vegetables. What are your thoughts on this ?
 
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I love my dopamine receptors. They keep me alive. Though sometime it's hard to feed them enough of what they want.

Did you get that text from an AI bot?
 
It's kind of strange that they merged all these threads together. Oh, Well if I'm going to talk about scientific topics they mind as well be in one Thread.
 
gpcr-1.webp


There are tons of neat images like this that researchers have made to easily visualize some of these pathways. This is a general image about G-protein coupled receptors (GCPRs)

If you want to find more just do an image search for the pathway you're interested in
 
MedicinalUser247 said:
It's kind of strange that they merged all these threads together. Oh, Well if I'm going to talk about scientific topics they mind as well be in one Thread.
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I merged these threads together because we can't have the front page filled with 0 response threads.

I'd be happy to leave separate them be if they had concise questions that generated any discussion, but you have a tendency to post a lot, and many of your posts feel like text dumps, where the reader needs to do a significant amount of work to understand, without any significant questions beyond "what are your thoughts".

I don't want to stifle your curiosity, but we are a community, and there is certainly something to be said for focusing on quality rather than quantity. If you have any other ideas on achieving that balance, let me know.

someguyontheinternet said:
41388_2017_Article_BFonc2016304_Fig1_HTML.jpg


Here's another for wnt
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God I fucking hate wnt signaling!

I've never gotten into development, and the only cancer stuff I know well is kinase driven. I also had a fairly annoying side project cloning a protein that anchors gsk3beta, but it really hated being expressed (even in hek293T and U2OS cells, which are our workhorses for biochemistry and imaging respectively).

However I used to get pretty bored with structural bio, but now it's like a big part of my project.
 
I was also about to ask what she was working on. GSK-3-beta is associated with Bipolar disorder and it's also being studied for Stroke related issues. I was also going to ask if she's working on gene therapy to try and cure Cancer as well.
 
someguyontheinternet said:
Honestly cancer pharm was the most boring, its all DNA interference and immune signaling antibodies, there are a couple targeted therapies but not many but that's also a snoozefest to me
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I like the chemistry of some chemo drugs, but most are pretty standard.

Unrelated, but this recent paper was extremely cool to me. A group coupled the glp1 peptide (which is very hot these days with ozempic et. al) to mk801 via a disulfide to make a circuit specific NMDA antagonist for glp1 receptor+ neurons. It's like what all the cool neuroscience work does with fancy conditional genetic models in a drug.

www.nature.com

GLP-1-directed NMDA receptor antagonism for obesity treatment - Nature

Unimolecular integration of NMDA receptor antagonism with GLP-1 receptor agonism effectively reverses obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.
www.nature.com www.nature.com
Open access
 
MedicinalUser247 said:
I was also about to ask what she was working on. GSK-3-beta is associated with Bipolar disorder and it's also being studied for Stroke related issues. I was also going to ask if she's working on gene therapy to try and cure Cancer as well.
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My lab works on signaling hubs and localization, I've been doing more basic science, but there are a couple of disease related projects going on.

Science is a pretty small world so I'm being intentionally vague so I don't dox myself here.
 
Mixed GLP-1 receptor agonism and NMDA receptor antagonism produces a weight loss drug ? That's interesting.
 
"MK-801 is widely used experimentally, but its clinical application is hampered by severe adverse effects. For example, chronic treatment with MK-801 promotes hyperthermia and hyperlocomotion."

This line from that paper is so hilariously understated.

MedicinalUser247 said:
Mixed GLP-1 receptor agonism and NMDA receptor antagonism produces a weight loss drug ? That's interesting.
Click to expand...
It's their method that really is cool to me, as they use a peptide (glp1) that gets internalized into the cell, and then the more reductive environment of the cytoplasm breaks the disulfide bonds freeing the mk801, so it only inhibits NMDA receptors at neurons that internalize it.

Im not quite sure how far this could be expanded (as you would need something to get internalized), but it is basically a pharmacological AND gate.
 
Skorpio said:
"MK-801 is widely used experimentally, but its clinical application is hampered by severe adverse effects. For example, chronic treatment with MK-801 promotes hyperthermia and hyperlocomotion."

This line from that paper is so hilariously understated.


It's their method that really is cool to me, as they use a peptide (glp1) that gets internalized into the cell, and then the more reductive environment of the cytoplasm breaks the disulfide bonds freeing the mk801, so it only inhibits NMDA receptors at neurons that internalize it.

Im not quite sure how far this could be expanded (as you would need something to get internalized), but it is basically a pharmacological AND gate.
Click to expand...
Oh that's pretty cool, if you can trigger beta arrestin you might be able to target specific GCPRs
 
Oh my god ! Know wonder why weight loss drugs are so expensive. I was looking at some of there chemical structures and there huge !
 
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