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Sedatives of the Future

Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC(50) = 58 +/- 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]fenobam binding to human mGlu5 receptors with a K(i) value of 6.7 +/- 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.
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Uncontrolled..
 
Relative abuse liability of indiplon and triazolam in humans : a comparison of psychomotor, subjective, and cognitive effects.

Indiplon is a positive allosteric GABAA receptor modulator that is under development for the treatment of insomnia. This study compared the abuse potential of indiplon, a compound with preferential affinity for GABAA receptors containing an alpha1 subunit, with triazolam in 21 volunteers with histories of drug abuse. Placebo, triazolam (0.25, 0.5, and 0.75 mg), and indiplon (30, 50, and 80 mg) were studied in counterbalanced order under double-blind conditions at two different residential research facilities. Both drugs impaired psychomotor and cognitive performance and produced similar dose-related increases in participant and observer ratings of drug strength. The onset of action of both drugs was rapid (30 min); however, the duration of action of indiplon (3-4 h) was shorter than triazolam (4-6 h). The profile of subjective effects of triazolam and indiplon were similar; however, a maximum of 52% of participants identified indiplon as a benzodiazepine or barbiturate, compared to 81% of participants after 0.75 mg triazolam. On participant-rated subjective effects relevant to sedation, the slope of the triazolam dose effect curve was significantly steeper than that of indiplon. Neither the largest doses of indiplon and triazolam nor the slope of the indiplon and triazolam dose effect curves were significantly different from each other on any of the same-day or next-day measures of positive drug effects or next-day measures of reinforcing effects. Together, these data suggest that although the abuse potential of indiplon is not different from that of triazolam at these doses, psychomotor and cognitive impairment after large doses of indiplon might be less.
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Indiplon was scheduled to IV by the DEA in 2006.
 
Just drink some HBr! I was browsing the Merck Index the other day and found out it used to be given as a sedative. Can anyone inform us about the simple bromides as sedatives?
 
Coriandrum sativum: evaluation of its anxiolytic effect in the elevated plus-maze.
Emamghoreishi M, Khasaki M, Aazam MF.

Department of Pharmacology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. [email protected]

The clinical applications of benzodiazepines as anxiolytics are limited by their unwanted side effects. Therefore, the development of new pharmacological agents is well justified. Among medicinal plants, Coriandrum sativum L. has been recommended for relief of anxiety and insomnia in Iranian folk medicine. Nevertheless, no pharmacological studies have thus far evaluated its effects on central nervous system. Therefore, the aim of this study was to examine if the aqueous extract of Coriandrum sativum seed has anxiolytic effect in mice. Additionally, its effect on spontaneous activity and neuromuscular coordination were evaluated. The anxiolytic effect of aqueous extract (10, 25, 50, 100 mg/kg, i.p.) was examined in male albino mice using elevated plus-maze as an animal model of anxiety. The effects of the extract on spontaneous activity and neuromuscular coordination were assessed using Animex Activity Meter and rotarod, respectively. In the elevated plus-maze, aqueous extract at 100 mg/kg showed an anxiolytic effect by increasing the time spent on open arms and the percentage of open arm entries, compared to control group. Aqueous extract at 50, 100 and 500 mg/kg significantly reduced spontaneous activity and neuromuscular coordination, compared to control group. These results suggest that the aqueous extract of Coriandrum sativum seed has anxiolytic effect and may have potential sedative and muscle relaxant effects.

PMID: 15619553 [PubMed - indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/sites/e...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
 
In my country (France), there are 2 anxiolytics commercialized that are not benzodiazepines, but with the same properties, I wonder if there are known derivatives of them, or if they can offer a staring point to create new tranquilizers or sedatives, they are:

Etifoxine
6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3, 1-benzoxazine
http://www.psychotropics.dk/usr_vie...e=All&backurlname=Search+Result&Catalogtype=A

Captodiame
2-[(p-butylthio)-a-phenylbenzyl)thio]-N, N-dimethyl-ethylamine hydrochloride
http://www.psychotropics.dk/usr_vie...e=All&backurlname=Search+Result&Catalogtype=A
 
It has been reported that, compared to lorazepam, captodiame improves the concentration and dexterity of individuals when driving, without inducing a tendency to drowsiness.
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That in particular interests me about the second one.
 
Synth

This masive paper has lots of GABAb agonist antagonist modulatrs with there synths

If only I could attach it

pm me if you want it
 
Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand.
Kita A, Kohayakawa H, Kinoshita T, Ochi Y, Nakamichi K, Kurumiya S, Furukawa K, Oka M.

Pharmacology & Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd, 33-94 Enoki, Suita 564-0053, Osaka, Japan. [email protected]

We investigated the ability of N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand, to produce anti-anxiety and antidepressant-like effects in various animal models. AC-5216 showed high affinity for MBRs prepared from rat whole brain (Ki 0.297 nm), rat glioma cells (IC50 3.04 nm) and human glioma cells (IC50 2.73 nm), but only negligible affinity for the other main receptors including central benzodiazepine receptors. AC-5216 produced anti-anxiety effects in the Vogel-type conflict test in rats, and in the light/dark box and social interaction tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg(-1), p.o., respectively. These effects of AC-5216 were antagonized by PK11195, an MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg kg(-1), p.o.) reduced the immobility time, and this effect was blocked by PK11195. AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitone-induced sleep in mice, even at doses as high as 1000 mg kg(-1), p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg(-1), AC-5216 (1-100 mg kg(-1), p.o.) produced no distinct change in the rat electroencephalogram. These results indicate that AC-5216 produces anti-anxiety and antidepressant-like effects that are mediated by MBR, but does not cause the side effects normally associated with conventional benzodiazepines. Hence, AC-5216 shows potential for the treatment of stress-related disorders including anxiety and depression. Copyright 2004 Nature Publishing Group

PMID: 15249420 [PubMed - indexed for MEDLINE]
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full text: http://www.nature.com/bjp/journal/v142/n7/full/0705681a.html

0705681f1th.gif
 
Hi all! I just bought Efron: Psychotropic drugs and related compounds. (1972) 2nd ed. 791p. And it cost 12 euros (posting included) from amazon.com. %)
It's kinda like Merck Index of psychoactive compounds.

Here's some scans:
https://rikki.fi/tajkor/bl/qualone1.jpg
https://rikki.fi/tajkor/bl/qualone2.jpg

That reference 984 is:
Lietz, W., & Matthies, H. Acta Biol. Med. German, 13, 591 (1964)

Lot of interesting stuff in that book.

They mention 4-methylaminorex under name McN-822
Action: Sympathomimetic
Human dose: 0,25mg
and source is Information supplied by McNeil Laboratories, Inc

And about methamphetamine: Hallucinogenic at large dose i.v. Hallucinogenic dose 40-60mg/i.v
 
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almost- said:
They mention 4-methylaminorex under name McN-822
Action: Sympathomimetic
Human dose: 0,25mg
and source is Information supplied by McNeil Laboratories, Inc

And about methamphetamine: Hallucinogenic at large dose i.v. Hallucinogenic dose 40-60mg/i.v
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is the dose they quote mg/kg because 4-MAR is active at 25-100mg?
I think methamphetamine is hallucinogenic in a psychotic crazy, they are all after me stealing my thoughts, kind of way.
 
Anyone familiar with benzodiazepines from Aspergillus ochraceus? I just ran into an article today, and haven't had a chance to research it enough to find out if any of the compounds are viable or even active.
 
vecktor said:
is the dose they quote mg/kg because 4-MAR is active at 25-100mg?
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No, human dose is 0,25mg, not 0,25 mg/kg. I think McNeil company was trying to bring that stuff to market as an asthma medicine. It's not mentioned as a stimulant, as a lot of compounds in the book are but as a sympatomimetic.
 
nuke said:
Today, after eating a pita with leftover avocado, and having eaten a lot of guacamole, I thought to myself that I felt rather sedated, but kind of dismissed it before getting curious and going to pubmed.

Apparently, persea americana (avocado) does actually have relaxant and anticonvulsant properties, especially in the leaf:

Anticonvulsant effect of Persea americana Mill (Lauraceae) (Avocado) leaf aqueous extract in mice.
http://www.ncbi.nlm.nih.gov/entrez/..._uids=16775810&query_hl=4&itool=pubmed_docsum

Antispasmodic effects of Persea cordata bark fractions on guinea pig ileum.
http://www.ncbi.nlm.nih.gov/entrez/..._uids=17174038&query_hl=4&itool=pubmed_docsum

Vasorelaxant action of aqueous extract of the leaves of Persea americana on isolated thoracic rat aorta.
http://www.ncbi.nlm.nih.gov/entrez/..._uids=15990249&query_hl=4&itool=pubmed_DocSum

More intriguing plants:
Analgesic and anticonvulsant properties of Tetrapleura tetraptera (Taub) (Fabaceae) fruit aqueous extract in mice.
http://www.ncbi.nlm.nih.gov/entrez/...Retrieve&dopt=abstractplus&list_uids=16372367

Anticonvulsant activity of Harpagophytum procumbens DC [Pedaliaceae] secondary root aqueous extract in mice.
http://www.ncbi.nlm.nih.gov/entrez/...Retrieve&dopt=abstractplus&list_uids=16464685
Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract.
http://www.ncbi.nlm.nih.gov/entrez/...Retrieve&dopt=abstractplus&list_uids=15742343

Anticonvulsant properties of the methanolic extract of Cyperus articulatus (Cyperaceae).
http://www.ncbi.nlm.nih.gov/entrez/...Retrieve&dopt=abstractplus&list_uids=11390127
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nuke said:
http://www.ncbi.nlm.nih.gov/sites/e...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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RE: these posts..

Any plant based sedation/anticonvulsant activity, etc. Could probably be put down to substituted flavones. There are quite alot of papers out there describing them and SAR etc.

Chrysin was one of the first to be discovered I believe. [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=2173925&dopt=AbstractPlus]

I also remember reading something about how polar substitutions - in certain positions - were necessary for GABAA binding, but I can only find this abstract at the moment.. [http://www.ncbi.nlm.nih.gov/sites/e...z.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]
 
Are any of these metaqualones going to avoid the analogue act in the US? Number 4 looks pretty interesting.
 
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