Group buy for novel anxiolytic. Research topic.
#31
Posted 29 October 2013 - 10:58 AM
First being, Fenobam because it is as effective if not more effective as benzos and won't lead to the same negative long term side effects, although in higher doses amnesia and other potential side effects are possible. Given it's relative ease of synthesis I want to find out how much would 100g cost initially.
Then the others aforementioned, Imidazenil, Emapunil, and Y-23684.
#32
Posted 29 October 2013 - 11:11 AM
#33
Posted 29 October 2013 - 11:38 AM
#34
Posted 29 October 2013 - 07:05 PM
OK, I dropped the interest in mGluR5 antagonists given some negative side effects, like delusions! Emapunil seems like a real good candidate and I hope I can get a quote for it. Anyone know the active dose range for it? At what doses is it effective?I'm glad to see there's still interest in this. However, upon a swift look, it would seem that mGluR5 antagonists may be psychotomimetic, which suffices to make me weary of MTEP and Fenobam. Y-23684 and Imidazenil have not been tested in humans (as far as I can see). Thus it would seem to me that Emapunil has the most favorable profile.
#35
Posted 29 October 2013 - 11:19 PM
I got this from a quick glance in the following pdf article: http://onlinelibrary...011.02166.x/pdf
#36
Posted 30 October 2013 - 02:32 PM
#37
Posted 05 November 2013 - 12:12 AM
#38
Posted 05 November 2013 - 06:25 AM
#39
Posted 05 November 2013 - 06:24 PM
Kappa agonist/mu antagonist: Levallorphan. A study said chronic use leads to antidepressant effect and ultimately euphoria.
Way-267 does look very good too.
Edited by celebes, 05 November 2013 - 06:38 PM.
#40
Posted 05 November 2013 - 07:46 PM
http://www.ncbi.nlm....pubmed/18692968
http://www.ncbi.nlm....pubmed/24129119
And of course there's still 7,8-dihidroxyflavone. TrkB downregulation might be less relevant when BDNF signalling is impaired. Irrespective of that, it does have a special efficacy in trauma.
#41
Posted 05 November 2013 - 11:05 PM
#42
Posted 08 November 2013 - 04:07 PM
The supplier for BPAP and Pitolisant is working on 7,8-dihydroxyflavone. I think he should give me word on it soon enough.Flesinoxan remains interesting, though the tolerability does makes it a riskier prospect. Unless the price was low enough to compensate for that?
http://www.ncbi.nlm....pubmed/18692968
http://www.ncbi.nlm....pubmed/24129119
And of course there's still 7,8-dihidroxyflavone. TrkB downregulation might be less relevant when BDNF signalling is impaired. Irrespective of that, it does have a special efficacy in trauma.
#43
Posted 10 November 2013 - 06:45 AM
http://en.wikipedia....-208,466
http://en.wikipedia......<br /><br />not perfect but maybe these could lead to finding others,
dunno why its adding html to my post...
Edited by golden1, 10 November 2013 - 06:47 AM.
#44
Posted 12 November 2013 - 01:21 AM
http://en.wikipedia.org/wiki/Abecarnil and Captodiamine.........http://jop.sagepub.c...10/930.abstract, http://link.springer...199917060-00005, http://www.ncbi.nlm....pubmed/15383182
Both seem to be promising. Let me know what you thinK.
#45
Posted 24 November 2013 - 12:18 AM
#46
Posted 24 November 2013 - 04:42 AM
Keep an eye out for that one. Worth researching.Great Thread, thank you yadayada! BNC210 might be interesting: http://en.wikipedia.org/wiki/BNC210
#47
Posted 14 December 2013 - 04:01 AM
Phenylethylidenehydrazine
https://en.wikipedia...lidenehydrazine
I just got a script for Nardil. But, if I can get PEH synthesized I won't have to deal with all the side effects of the parent compound. . . Thoughts? Sounds better than taking a benzo.Phenylethylidenehydrazine (PEH) is an inhibitor of the enzyme GABA transaminase (GABA-T).[1][2] It is a metabolite of the antidepressant phenelzine and is responsible for its elevation of GABA concentrations.[1] PEH likely plays a significant role in phenelzine's high efficacy in treating anxiety disorders.
#48
Posted 14 December 2013 - 04:10 AM
#49
Posted 14 December 2013 - 10:17 AM
I think I found it.
Phenylethylidenehydrazine
https://en.wikipedia...lidenehydrazineI just got a script for Nardil. But, if I can get PEH synthesized I won't have to deal with all the side effects of the parent compound. . . Thoughts? Sounds better than taking a benzo.Phenylethylidenehydrazine (PEH) is an inhibitor of the enzyme GABA transaminase (GABA-T).[1][2] It is a metabolite of the antidepressant phenelzine and is responsible for its elevation of GABA concentrations.[1] PEH likely plays a significant role in phenelzine's high efficacy in treating anxiety disorders.
I would participate in a PEH group buy. Not sure though if PEH alone will be enough to tackle anxiety disorders. It's hard to tell how much of the anxiolytic effects of Nardil are indeed due to PEH. When I look at this list of other GABA-T inhibitors:
http://en.wikipedia....inase_inhibitor
then I have to say that these drugs are not particularly known as strong anxiolytics. Rather mild ones at best.
Anyhow, at least it's a substance that has been used for decades in humans even though as part of the parent molecule Phenelzine. If the price is right for the synthesis then I am in.
Edited by focus83, 14 December 2013 - 10:19 AM.
#50
Posted 15 December 2013 - 01:19 AM
I'm still partial to oxytocinergics, but if we're not going down that rabbit hole yet I'd love to see how this stuff compares to etizolam as anti-"geez, I'm stressed out like all hell today" drug on top of propranolol.
#51
Posted 16 December 2013 - 09:05 AM
Dopamine reuptake inhibition and anticholinergic? Sounds like a distant cousin (effects-wise) of bupropion (wellbutrin). No thanks.Bromantane looks interesting, both a stimulant and an anxiolytic with a very good safety profile: http://en.wikipedia....wiki/Bromantane
Although this is not a group buy candidate, It could be a good solution to the anxiety problem.
PEH sounds interesting, but please take a look at side effects of the drugs in this class..
From Wikpedia article on Vigabatrin:
Adverse effects
Central nervous system
Out of 2,081 subjects, somnolence (12.5%), headache (3.8%), dizziness (3.8%), nervousness (2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%), aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision abnormalities (1.6%), confusion (1.4%), insomnia (1.3%), impaired concentration (1.2%), personality disorder (1.1%).[1] Out of 299 children, 33 (11%) became hyperactive.[1]
Some patients develop psychosis during the course of vigabatrin therapy,[10] which is more common in adults than in children.[11] This can happen even in patients with no prior history of psychosis.[12] Other rare CNS side effects include anxiety, emotional lability, irritability, tremor, abnormal gait, and speech disorder.[1]
Gastrointestinal
Abdominal pain (1.6%), constipation (1.4%), vomiting (1.4%), and nausea (1.4%). Dyspepsia and increased appetite occurred in less than 1% of subjects in clinical trials.[1]
Body as a Whole
Fatigue (9.2%), weight gain (5.0%), asthenia (1.1%).[1]
Teratogenicity
A teratology study conducted in rabbits found that a dose of 150 mg/kg/day caused cleft palate in 2% of pups and a dose of 200 mg/kg/day caused it in 9%.[1] This may be due to a decrease in methionine levels, according to a study published in March 2001.[13] In 2005, a study conducted at the University of Catania was published stating that rats whose mothers had consumed 250–1000 mg/kg/day had poorer performance in the water maze and open-field tasks, rats in the 750-mg group were underweight at birth and did not catch up to the control group, and rats in the 1000 mg group did not survive pregnancy.[14]
There is no controlled teratology data in humans to date.
Sensory
In 2003, vigabatrin was shown by Frisén and Malmgren to cause irreversible diffuse atrophy of the retinal nerve fiber layer in a retrospective study of 25 patients.[15] This has the most effect on the outer area (as opposed to the macular, or central area) of the retina.[16] Visual field defects had been reported as early as 1997 by Tom Eke and others, in the UK. Some authors, including Comaish et al. believe that visual field loss and electrophysiological changes may be demonstrable in up to 50% of Vigabatrin users.
The retinal toxicity of vigabatrin can be attributed to a taurine depletion.[17]
......No thanks! I would rather take a GABA agonist than deal with those things ^ Also apparently gaba transaminase inhibitors can cause long-term, irreparable side effects. I think messing with this enzyme sounds scary. Although I will admit I still have some interest in rosemarinic acid since it seems to be less aggressive/less potent. And it's natural.
I have a fantasy of discovering a novel anxiolytic that does not have direct agonist properties for dopamine receptors or GABA receptors. An allosteric modulator would be much better, but may be weaker. I'm interested in metabotropic glutamate receptors 2/3, and have a desire to find a non-pharmaceutical positive allosteric modulator for them. Eglumegad is a direct agonist, but I suspect it has properties of withdrawal and downregulation/desensitization of the recepors it binds to, since it's a pharmaceutical antipsychotic/anxiolytic.
There has to be something that can regulate or "teach" the HPA to behave better in the long term. Something that you could take for like 2 months, and it would somehow rehabilitate your brain. This is wishful thinking, but the possibility is certainly there. Too bad pharmaceutical companies will never find such an agent due to their primary interest in drugs which must be taken daily for years, which manage symptoms instead of repair the underlying neural networks.
Edited by katuskoti, 16 December 2013 - 09:06 AM.
#52
Posted 16 December 2013 - 09:13 AM
Yes, I also have a high interest in oxytocin agonists. Apparently certain drugs used to induce labor in pregnancy may fit this class (more similar to vasopressin), but obviously the side effects are very concerining!I think oxytocin agonists are an interesting target. WAY-267,464 is highly selective and anxiolytic in mice.
Also on the non-RC side of things, I've found propranolol, afobazole and niacinamide to all be good non-benzo anxiolytics. Oxytocin also, but short acting as an anxiolytic. Buspirone to some degree, but less so.
Niacinamide is a good mention. I believe it is a GABA agonist but must be a little more benign, seeing as it is widely available and causes no amnesia or withdrawal or anything.
#53
Posted 16 December 2013 - 06:33 PM
#54
Posted 16 December 2013 - 11:34 PM
J Physiol Anthropol. 2012 Oct 29;31:28. doi: 10.1186/1880-6805-31-28.
Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses.
Yoto A, Motoki M, Murao S, Yokogoshi H.
Author information
BACKGROUND:
L-theanine, an amino acid contained in green tea leaves, is known to block the binding of L-glutamic acid to glutamate receptors in the brain, and has been considered to cause anti-stress effects by inhibiting cortical neuron excitation. Both L-theanine and caffeine, which green tea contains, have been highlighted for their beneficial effects on cognition and mood.
METHODS:
In this study, we investigated the effects of orally administered L-theanine or caffeine on mental task performance and physiological activities under conditions of physical or psychological stress in humans. Fourteen participants each underwent three separate trials, in which they orally took either L-theanine + placebo, caffeine + placebo, or placebo only.
RESULTS:
The results after the mental tasks showed that L-theanine significantly inhibited the blood-pressure increases in a high-response group, which consisted of participants whose blood pressure increased more than average by a performance of a mental task after placebo intake. Caffeine tended to have a similar but smaller inhibition of the blood-pressure increases caused by the mental tasks. The result of the Profile of Mood States after the mental tasks also showed that L-theanine reduced the Tension-Anxiety scores as compared with placebo intake.
CONCLUSIONS:
The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood-pressure increase in high-stress-response adults. PMID: 23107346
and
Pharmacol Biochem Behav. 2013 Oct;111:128-35. doi: 10.1016/j.pbb.2013.09.004. Epub 2013 Sep 16.
Anti-stress effect of theanine on students during pharmacy practice: positive correlation among salivary α-amylase activity, trait anxiety and subjective stress.
Unno K, Tanida N, Ishii N, Yamamoto H, Iguchi K, Hoshino M, Takeda A, Ozawa H, Ohkubo T, Juneja LR, Yamada H.
Author information
PURPOSE:
Theanine, an amino acid in tea, has significant anti-stress effect on experimental animals under psychosocial stress. Anti-stress effect of theanine on humans was evaluated in 5th-year university students during pharmacy practice.
METHOD: The study design was a single-blind group comparison and participants (n=20) were randomly assigned to theanine or placebo groups. Theanine or placebo (lactose) tablets (200 mg, twice a day, after breakfast and lunch) were taken from 1 week prior to the pharmacy practice and continued for 10 days in the practice period. To assess the anxiety of the participants, the state-trait anxiety inventory test was carried out before the pharmacy practice. Salivary α-amylase activity (sAA) was measured as a marker of sympathetic nervous system activity.
RESULTS: In the placebo-group, sAA in the morning (pre-practice sAA) was higher than in theanine-group during the pharmacy practice (p=0.032). Subjective stress was significantly lower in the theanine-group than in the placebo-group (p=0.020). These results suggest that theanine intake had anti-stress effect on students. Furthermore, students with higher pre-practice sAA showed significantly higher trait anxiety in both groups (p=0.015). Similarly, higher pre-practice sAA was correlated to shorter sleeping time in both groups (p=0.41×10(-3)).
CONCLUSION: Stressful condition increased the level of sAA that was essentially affected by individual trait anxiety. The low levels of pre-practice sAA and subjective stress in the theanine-group suggest that theanine intake suppressed initial stress response of students assigned for a long-term commitment of pharmacy practice.
© 2013. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
ANS, Anti-stress, Chronic stress, HPA, STAI, Salivary α-amylase, Subjective stress, Theanine, Trait anxiety, VAS, autonomic nervous system, hypothalamus–pituitary–adrenal, post-practice sAA, pre-practice sAA, sAA, sAA in the evening, sAA in the morning, salivary α-amylase activity, the state–trait anxiety inventory, visual analog scales PMID: 24051231
Edited by malbecman, 16 December 2013 - 11:36 PM.
#55
Posted 17 December 2013 - 01:07 AM
Had a quick look, they all seem to good to be existing.. why aren't those chems not further developed by pharma's??
Edited by YoungS, 17 December 2013 - 01:21 AM.
#56
Posted 19 December 2013 - 02:02 AM
I'm using Lorazapam as a stop-gap measure until I can find something less cognitively impairing.
#57
Posted 19 December 2013 - 02:11 AM
#58
Posted 19 December 2013 - 02:26 AM
I'm going to try and start a group buy for two compounds:
partial agonists are better than full agonists:
https://en.wikipedia.org/wiki/ELB-139
then maybe
https://en.wikipedia.org/wiki/Y-23684
#60
Posted 19 December 2013 - 06:36 AM
I posted about it over here:Lanicemine: http://en.wikipedia.org/wiki/AZD6765
http://www.longecity...sive-symptomes/
Has too short lived effects.
Also tagged with one or more of these keywords: gaba, alpha, glutamate
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