SNRB-OX is a proprietary Optimized Xtract Scientifically Engineered Selective NMDA Receptor Subunit 2B (NR2B) Low-Efficacy Weak Partial Agonist with Functional Antagonist activity.
Research Indications: antidepressant, anxiolytic, neuroprotectant, neuroregenerative, and congnition enhancement research.
Supplied in solution
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SNRB-OX Scientifically Engineered NMDA Receptor Subunit 2B (NR2B) Selective Functional Weak Partial Agonist (Functionally Antagonist)
Sources: Proprietary source
SNRB-OX is a highly selective selective NMDA receptor subunit 2B (NR2B) functional antagonist (technically a low efficacy very weak partial agonist, IA = 7%) demonstrating a half-life of ~12 hours.
Format of Supply:
In solution. Further dilution via ethanol/alcohol and/or glycerine is viable.
Pronounced and rapid onset of effects are seen demonstrated within animal antidepressant models and anxiolytic models. Demonstrates equivalent efficacy and >1000% potency as assayed against CERC-301 as the reference standard. No adverse effect or behaviors were demonstrated within all models assayed.
LTP was markedly enhanced at therapeutically relevant doses. Markers for cognition, learning, and memory enhancement are demonstrated at these doses, whereas higher doses yield an impairment of such.
Theorized Human Optimization Protocol:
SNRB-OX is theorized to display in future clinical trials rapid prolonged/long-acting antidepressant effects on par with ketamine, but with no psychotomimetic effects. Potential dose arms are to be at 0.125, 0.250mg, and 0.500mg, per day via any orally viable format with indication to administer the dosing at bedtime. Within all factors it appears to demonstrate potential to express highest potency, efficacy, and therapeutic index (safety and minimized adverse effect potential). Sublingual dosing would appear to require ~50-70% of oral dose.
Cognitive enhancement is also preceived to be a benefit within neurogenerative, neuroprotectant, and neurogenic capacities.
USAGE: For Research Use Only! Not For Use in Humans
Introducing SNRB-OX Selective NRB2 Weak Functional Partial Agonist (Functional Antagonist)
We are very pleased to have finally completed refinement and production of a very highly pursued SEP-OX Optimized Xtract SNRB-OX. This Xtract was screened for and developed within the goals of providing a potent, high efficacy glutamatergic modulating agent that affords the positive neurological effects as seen with Ketamine, but with no potential for any adverse effects or psychotomimetic effects.
Such agents of this class foster a marked increase in BDNF and work via potent BDNF pathway signaling modulation. One main benefit this pathway fosters is rapid and potent synaptogenesis. This affords a potent means to restore superior functionality to the brain in many core aspects.
Within that, SNRB-OX demonstrates in animal models assayed for such, the benefits of sound rapid-acting antidepressant efficacy, cognitive enhancement efficacy, and neuroprotective efficacy.
Assays within mice models showed an effective dose range of 0.075mg/kg to 0.125mg/kg per oral administration within all models assayed as relates to assessing the efficacy for the given challenges. Potentials for future human clinical trials would suggest dosing at 0.5mg to 1.5mg q.d.
From all appearances this appears to have potential to be a breakthrough highly potent, rapid-acting, ketamine-like antidepressant with minimal potentials for any adverse effects of any nature; devoid of such potential adverse effects as seen as intrinsic with ketamine, analogues thereof, and most all NMDA antagonist directed agents of this class. Within that, such appears to potentially afford a most potent therapeutic efficacy and a highest degree of therapeutic index. Notably, potent neuroprotective and cognition enhancing benefits are as well demonstrated, as expected as within what is seen indicated as to benefits from agents with this profile.
The case for selective NMDA glutamatergic modulation for promotion of BDNF signaling and strong therapeutic efficacy within the spectrum of depressive disorders and related psychoneurological disorders affected by atrophy of synaptic 'tone' and related cerebroatrophy is more fully elaborated upon as related herein.
Although ketamine is usually associated to its dissociative (psychotomimetic) profile, it has been and still remains the paradigmatic compound for glutamatergic based antidepressants (for meta-analysis see Caddy, Giaroli, White, Shergill & Tracy, 2014). Traditional antidepressants predominantly increase serotonergic and/or noradrenergic intrasynaptic availability which ultimately restores normal glutamatergic transmission. Alternatively, Ketamine increases glutamate intrasynaptic availability directly. Ketamine has been shown to improve depression symptoms as measured in animal models in the test of learned helplessness, forced swim test and novelty suppressed feeding test. In humans, subanesthetic doses of ketamine improve over classic monoamine antidepressants in three major ways:
I.) It has therapeutic effects as an acute treatment (single administration), whereas traditional antidepressants require repeated administration to produce therapeutic effects.
II.) It has fast acting therapeutic effects (within 24-48 hours) as opposed to traditional antidepressants, which usually take 6-8 weeks to produce amelioration with similar rates of symptomatic relief.
III.) It has been shown to ameliorate symptoms of monoamine treatment resistant depression.
Synapse atrophy is a morphological landmarks of depression within the prefrontal cortex (PFC) and the hippocampus. A circuitry impairment leading to impaired neurocomputation. Among others, PFC function underlies flexible adaptive behavior, suppression of "thoughtless" emotional response and goal oriented recollection of memories. Depressed PFC and hippocampus computational power may blunt the capacity to learn new adaptive behaviors to overcome negative circumstances (e.g. learn new abilities to get a better job), lose control over subcortical short term coping behaviors (e.g. suicide, alcohol abuse) or redound on spontaneous intromissions of negative memories (e.g. selective memory for failures) and so forth.
Ketamine is a non-selective NMDA receptor (NMDAR) channel blocker, which is apparently at odds with promoting glutamatergic transmission. At sub-anesthetic dose, ketamine is thought to achieve its effects by decreasing excitatory input into subsets of inhibitory interneurons. This relieves inhibitory input onto excitatory pyramidal cells and increased glutamate release from same. Amidst increased glutamatergic transmission, AMPAR depolarization opens voltage gated calcium channels (VGCC) and which trigger calcium-dependent intracellular signaling. Through AMPAR, ketamine antidepressant effects have been shown to depend on (for review see Machado-Vieira, Salvadore, DiazGranados & Zarate, 2009; Schepisi, Sabatini & Nencini, 2014):
Activation of mTOR
Activated by Akt, a main inhibitor of pro-apoptotic signaling
Activation of BDNF-TrkB (release, local translation and transcription)
Long term neuroprotection, pre and post-synaptic potentiating, long term potentiating, homeostatic plasticity...
Inhibition of eEF2 kinase (also known as CaMKIII)
Prevents translation of BDNF among others
Inhibition of GSK-3
Apoptotic and long term depression signaling.
BDNF is thought to be the main responsible for the long-term neuroprotective effects of NMDAR activity (for review see Georgiev, Taniura, Kambe & Yoneda, 2008). BDNF-TrkB activity has been shown to activate CaMKII/IV, Ras/ERK and PI3K/Akt pathways promoting protein synthesis independent (e.g. BAD inhibition, presynaptic vesicle docking, NR2B phosphorilation...), translation dependent (e.g. PSD-95, NR, Arc, α-CaMKII...) and transcription dependent (e.g. CREB, c-FOS...) synaptic plasticity and neuroprotection. BDNF has been shown to enhance memory and its dishomeostasis implicated in neurodegenerative and neuropsychiatric disorders as well as in normal ageing.
A therapeutic limitation of ketamine are its dissociative effects and its potential to mimic psychotic-like symptoms during substance abuse. Ketamine is a non-competitive NMDAR channel blocker but studies have shown that selective NR2B subunit NMDAR antagonists also sustain antidepressant effects (e.g. Maeng et al., 2007). Along these lines, the NR2B antagonist CP-101,606 was shown to profile the effects of ketamine in treatment resistant major depressive disorder. Howbeit, it did have dissociative effects shortly after administration which, nonetheless, were followed by remission (Preskorn et al., 2008). Alternatively, another NR2B subunit selective antagonist, MK-0657 (now CERC-301), was seemingly dissociative free in a small study in humans with treatment resistant major depressive disorder (Ibrahim et al., 2012 ). CERC-301 is in second phase clinical trials as an antidepressant.
Therein, within agents that modulate the glutamatergic system in a like manner, but do so in a manner devoid of dissociative activity,are seemingly at this juncture the most optimized agents for potent and rapid-onset alleviation of the symptomatology of depression, in particular especially treatment resistant depression and 'complex', major depressive disorders. SNRB-OX SEP-OX Optimized Xtract is a first-in-class extract that fulfills this criteria and exhibits a highest degree of therapeutic index, as is within the goal of all SEP-OX Optimization Research.
Caddy, C., Giaroli, G., White, T. P., Shergill, S. S., & Tracy, D. K. (2014). Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology, 4(2), 75–99. doi:10.1177/2045125313507739
Georgiev, D. D., Taniura, H., Kambe, Y., & Yoneda, Y. (2008). Crosstalk between brain-derived neurotrophic factor and N-methyl-D-aspartate receptor signaling in neurons, (November), 17–27.
Ibrahim, L., DiazGranados, N., Jolkovsky, L., Brutsche, N., Luckenbaugh, D. A., Herring, W. J., & Zarate Jr, C. A. (2012). A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. Journal of clinical psychopharmacology, 32(4), 551.
Machado-Vieira, R., Salvadore, G., Diazgranados, N., & Zarate, C. a. (2009). Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacology & Therapeutics, 123(2), 143–50. doi:10.1016/j.pharmthera.2009.02.010
Maeng, S., Zarate, C. a, Du, J., Schloesser, R. J., McCammon, J., Chen, G., & Manji, H. K. (2008). Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biological Psychiatry, 63(4), 349–52. doi:10.1016/j.biopsych.2007.05.028
Preskorn, S. H., Baker, B., Kolluri, S., Menniti, F. S., Krams, M., & Landen, J. W. (2008). An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. Journal of clinical psychopharmacology,28(6), 631-637.
Schepisi, C., Sabatini, D., & Nencini, P. (2014). Neurobiological substrate of ketamine- induced antidepressant effects Clinical evidences on the potential antidepressant activity of ketamine, 55–60.
Glutamatergic neurotransmission has been implicated in affective disorders, possibly through the modulation of monoaminergic mechanisms. The aim of this study was to investigate the effect of coadministration of the noncompetitive NMDA antagonist dizocilpine (MK-801) with different, primarily noradrenergic and serotonergic antidepressants on forced swimming test (FST) and open-field behavior in rats. Acute administration of dizocilpine at doses of 0.02- 0.1 mg/kg did not show any effect in the open-field test or FST. Acute administration of citalopram (5 mg/kg), fluoxetine (20 mg/kg), desipramine (20 mg/kg) and maprotiline (20 mg/kg) did not influence FST, although coadministration of dizocilpine with serotonergic but not noradrenergic antidepressants caused a significant reduction of immobility. In the open-field test, fluoxetine had no effect on horizontal activity but significantly reduced the number of rearings. The coadministration of dizocilpine with fluoxetine elicited significant horizontal locomotor activation and attenuated the effect of fluoxetine on vertical activity. The combined administration of other antidepressants with dizocilpine tended to increase horizontal activity similar to that recorded with fluoxetine plus dizocilpine, but these effects were not statistically significant. Thus, the present results indicated that the coadministration of serotonergic antidepressants with NMDA receptor antagonists may induce faster and more pronounced antidepressant activity when compared to treatment with antidepressants alone. In contrast, the NMDA antagonists did not potentiate the antidepressant-like effects of noradrenergic antidepressants.
Mostly soluble within hydroethanolic solutions at up to 30mg/ml
Supplied in hydroalcoholic solution - dilution as desired optimum with ethanol and glycerine.
E-mail for details regarding bulk purchases at TLR@teamtlr.com
USAGE: For Research Use Only! Not For Use in Humans