https://en.wikipedia.org/wiki/Zuranolone
Won't that result in benzodiazepine esque dependence and withdrawals considering its same receptor?
Title: Structure Based Design of PDE4 Allosteric Modulators
DOI: 10.1055/s-0032-1304234
URl: Thieme E-Journals - Hormone and Metabolic Research / Abstract (thieme-connect.com)
Hello, I've been prescribed Clonazepam 1ng twice daily for about 13 years now. After a out 8 years I asked twice to have my dosage increased by 1mg every 8hours instead of 1mg every twelve hours. I was treated like a non human drug addict although I have extreme panic disorder and Tourettes syndrome. Also on both sides of family I have aunt's and uncles with extreme agoraphobia and panic disorder. I ended up having to find other non illegal methods of acquiring positive allosteric modulators. I do NOT like having to do this without a doctor's supervision, but I have had the full myriad of W/D effects not limit to seizures, delirium tremens, extremely hight heart rate and blood pressure, and I do not feel that I will be able to survive the extreme W/D's. I don't like how I was put on a medication that has helped me live a normal life but after 8 years I hadn't asked for an increase untill the last 2 months, after 13 years on the same dosage. I have understanding GP who assures me he will never take my script away, he is a good man he is just worried of causing more harm. I'm not sure if I need to visit a Toxicologist along with my neurologist who I can only see at most twice a year due to my Insurance. I just want to be able to live normally again, I have been told by nephrologists, UC D Toxicologist at the ER and a GP with PHd that the likelihood of me going off benzos is basically an impossibility due to the length of treatment and organic changes on a CT scan. I just want to get my dosage right so I can take care of my responsibilities, I was a student at college as well as taking care of my elderly mother and younger brother with schizoaffetive disorder and diabetes, I am having a difficult time taking care of myself and loved ones who need me, I just wonder if there's a way to get help. I do not want to titerate just get a proper dosage.
Thanks If you read, feel free to message me.
What is glycine?
In the context of today’s fact of the day, glycine is known as an inhibitory neurotransmitter. When glycine attaches to glycine receptors in the nervous system it agonizes the receptor and allows a chloride ion to enter the neuron, reducing its potential for action. This can be seen as a “calming” effect on the nervous system [1].
Strychnine?
You’ve probably heard of this poison, strychnine. Strychnine in the human body is the antithesis of glycine. Strychnine is known as a glycine antagonist. What this means is that when strychnine binds to glycine receptors it prevents the normal inhibitory actions of glycine. So when strychnine binds, it prevents the pore from opening and allowing a chloride ion through. This causes the cell to be hyperpolarized and increases it’s possibility of firing an action. If you get enough strychnine to bind to enough glycine receptors it can cause many rather unpleasant reactions such as generalized muscle spasms and seizures as well as brain damage, kidney failure and ultimately death in high enough doses [2].
How does kava work in regards to glycine?
The constituents of kava were shown to be effective in the reversal of strychnine toxicity in mice [3]. This means there is some competitive inhibition between kavalactones and strychnine. Kavain was shown to have a high affinity to glycine receptors and also acts as an antagonist, similar to strychnine. Researchers theorize that kava lacks toxicity similar to strychnine in this regard due to its ability to positively modulate GABA-A receptors as well.
Our facts of the day have covered positive allosteric modulation by kavain at the GABA-A receptor, and now we see kavain as a negative allosteric modulator at the target of glycine receptors. “Allosteric'' in this sense means that kavain exerts its action by means other than binding to the orthosteric, or endogenous binding site of the glycine receptor. Similar to how benzodiazepines bind to allosteric sites on GABA-A, so it is thought that kavain may have its own set of specific sites at which to bind as well. These sites have yet to be discovered specifically for the glycine receptor.
What does this mean to the kava experience?
It may not mean all that much to the physical experience of kava, seeing that not only are glycine receptors affected, but also GABA-A receptors. Where glycine receptor antagonism would cause an increase in the possibility of the neuron firing and may increase excitability,
... keep reading on reddit ➡Today we’re going to return to one of our old topics to fill in some gaps. GABA-A. In the past I’ve described kavalactone’s binding ability to GABA as “enhancing” natural GABA to bind to its receptor. After further research, while accurate in simple terms, it is not the more complete picture. Kavalactones do enhance binding of GABA to the GABA-A receptor, and they do it in a familiar process. Also to address some misconceptions, kavain DOES likely bind at GABA-A, but not the way we observe for other compounds.
We’ll need to define a few words here.
Orthosteric ligand (drug): This is a chemical that interacts with the same binding site as the natural endogenous chemicals found in our body (Jakubík et al. 2019). In this instance the natural chemical would be the neurotransmitter, GABA.
Allosteric ligand (drug, also known as a modulator): This is a chemical that works by modifying how the receptor behaves when it has been bound to an orthosteric ligand. The allosteric binding sites are distinctly separate from the site of the main transmitter, GABA’s binding site.
Positive allosteric modulator (PAM): a modulating chemical that binds to an allosteric site and increases the affinity or the efficacy of an agonist for that receptor (Kenakin 2017). Again, in this instance GABA will be the agonist that is being affected when it binds to the GABA-A receptor.
The positive allosteric modulator in this instance will be kava. Other examples of PAMs are drugs like alprazolam (xanax). Xanax binds to the benzodiazepine allosteric site on the GABA receptor and influences the receptor to allow the channel in the center to be open for longer periods of time, or more frequently. Kava extracts and pure kavalactones have been shown to enhance the effect when a natural neurotransmitter binds to that site similarly, but not identically to alprazolam, as kavalactones have not been shown to bind at the benzodiazepine site.
In 2016 a study was completed on the effects of kavain at various GABA-A subunit receptor sites (areas where allosteric chemicals bind). Kavain was found to positively modulate all receptors, regardless of subunit composition. It highly infers the p
... keep reading on reddit ➡Using a Positive allosteric modulator increases the response to agonists.
Has anyone tried this? I'll be running some tests with it.
Inspired by this study which used "Combination of Nicotine with Galantamine may have enhanced therapeutic effect in patients with Alzheimer's disease."
https://staticweb.bmj.com/clinmed/original/2002080001v1/Comb__nic_plus_galant_in_AD-YES.htm
Positive allosteric modulator:
Galantamine.
Agonist:
Nicotine.
Phenylpiracetam.
GTS-21.
I propose Phenylpiracetam and Galantamine as the best stack to utilize this mechanism. See studies below.
This should be a potent pre-workout aswell, as both activate muscle type nicotinic acetylcholine receptors.
What Galantamine was missing all along may have been an agonist.
Studies:
https://www.nature.com/articles/1301256
"Galantamine (3 mg/kg p.o.) significantly increased the extracellular dopamine release in the hippocampus of saline- and Aβ25−35-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC29386/
"Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with Galantamine."
http://europepmc.org/article/PMC/1576175
"Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. "
"Phenylpiracetam binds to α4β2 nicotinic acetylcholine receptors in the mouse brain cortex with IC50 = 5.86 μM.[6]."
https://link.springer.com/article/10.1007/s00213-019-05363-4
This may reflect specific nAChR subtype involvement, or additional pharmacological actions of galantamine may have overshadowed similar interactions on other measures. The finding suggests that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle."
https://www.jneurosci.org/content/25/8/1992.short
"Galantamine Activates Muscle-Type Nicotinic Acetylcholine Receptors."
https://fscimage.fishersci.com/images/D00599~.pdf
"Galantamine is a potent allosteric potentiating ligand (APL) of human alpha3beta4, alpha4beta2, and alpha6beta4 nicotinic receptors (nAChRs). Galantamine potentiates agonist responses of the four nAChR subtypes studied.
These studies support our previous proposal that the therapeutic action of galantamine is mainly produced by its sensiti
... keep reading on reddit ➡
https://en.wikipedia.org/wiki/Zuranolone
Zuranolone (INN;[1] developmental code names SAGE-217, S-812217) is an investigational medication which is under development by SAGE Therapeutics for the treatment of depressive disorders and a variety of other indications.[2][3] It is a synthetic, orally active, inhibitory pregnane neurosteroid, and acts as a positive allosteric modulator of the GABAA receptor.[2][3][4] The drug was developed as an improvement of allopregnanolone (brexanolone) with high oral bioavailability and a biological half-life suitable for once-daily administration.[3] As of October 2019, zuranolone is in phase III clinical trials for major depressive disorder, postpartum depression, and insomnia and is in phase II clinical studies for bipolar depression, essential tremor, and [Parkinson's disease](https://en.wikipedia.org/wiki/Parkinson
... keep reading on reddit ➡Hi all,
As far as I'm aware, the most potent anxiolytic drugs available are gaba a agonists that increase inhibitory transmission (alcohol, benzodiazepines...).
Conversely, gaba antagonists such as flumazenil have an opposite effect, with the potential to cause seizures at higher doses.
I was looking into Quercetin, described by multiple sources as a negative allosteric modulator at the gaba a receptor
"Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. "
Quercetin as negative allosteric modulator.
However, other papers conclude that quercetin likely exerts an anxiolytic effect through the gabaergic system, and that that effect is BLOCKED by co administration of a gaba a agonist; *"As shown in Fig. 3 , the anxiolytic-like effects of quercetin were not antagonized either by WAY-100635 (0.3 mg/kg) or flumazenil (10 mg/kg). However, interestingly, the anxiolytic-like effects of quercetin (5 mg/kg) were * *blocked by TACA (20 mg/kg), a GABA A-ρ receptor potent agonist."
How does this work? How can the administration of a gaba agonist block an anxiolytic effect? How can the inhibition of gabaergic transmission have an anxiolytic effect, rather than the opposite such as is the case with flumazenil?
Thank you.
After asking about Michael Jackson's drugs, now i want to know why benzos and alchool produce sleep which is clinically unrestful whereas substances like gabapentin and phenibut seem to truly rest the mind?
Nature employs sulfur switches, i.e. redox‐active disulfides, to kinetically control biological pathways in a highly efficient and reversible way. Inspired by this mechanism we describe here a DNA‐based synthetic nanodevice that acts as a sulfur switch and can be temporally controlled though redox regulation. To do this we rationally designed disulfide DNA strands (modulators) that hybridize to a ligand‐binding DNA nanodevice and act as redox‐active allosteric regulators inducing the nanodevice to release or load its ligand. Upon reduction, the allosteric modulator spontaneously de‐hybridizes from the nanodevice and, as a result, its effect is transient. The system is reversible and has an unprecedented high tolerance to waste products and displays transient behavior for over 40 cycles without significant loss of efficiency. Kinetic control of DNA‐based ligand‐binding nanodevices through purely chemical reactions paves the way for temporal regulation of more complex chemical pathways.
https://ift.tt/33FPCWB
Title: Structure Based Design of PDE4 Allosteric Modulators
DOI: 10.1055/s-0032-1304234
URl: Thieme E-Journals - Hormone and Metabolic Research / Abstract (thieme-connect.com)
We describe a DNA‐based nanodevice that acts as a sulfur switch and can be temporally controlled through redox cycles of a disulfide‐linked allosteric modulator. The system has an unprecedented high tolerance to waste products and displays transient behavior for over 40 cycles without significant loss of efficiency. The approach is reversible and allows the transient loading and release of a ligand upon successive reduction and oxidation of the modulator.
Abstract
Nature employs sulfur switches, that is, redox‐active disulfides, to kinetically control biological pathways in a highly efficient and reversible way. Inspired by this mechanism, we describe herein a DNA‐based synthetic nanodevice that acts as a sulfur switch and can be temporally controlled though redox regulation. To do this, we rationally designed disulfide DNA strands (modulators) that hybridize to a ligand‐binding DNA nanodevice and act as redox‐active allosteric regulators inducing the nanodevice to release or load its ligand. Upon reduction, the allosteric modulator spontaneously de‐hybridizes from the nanodevice and, as a result, its effect is transient. The system is reversible and has an unprecedented high tolerance to waste products and displays transient behavior for over 40 cycles without significant loss of efficiency. Kinetic control of DNA‐based ligand‐binding nanodevices through purely chemical reactions paves the way for temporal regulation of more complex chemical pathways.
https://ift.tt/33FPCWB
