This thread will focus solely on the GABA-A receptor and the various unique ligands that bind to it. You see, I've been looking around for a solution to my insomnia. Not wanting to go the Michael Jackson route, I've been looking at both old and new GABAergic drugs which I might use as sleep aids. In the course of my research, I've come across literally dozens of interesting looking compounds- this isn't a target known a tightly defined SAR. This is what makes it so interesting.
Having many different subunit combinations means that there are many different types of GABA receptor, and with each unique combination there's a slightly different binding pocket. Compounds with high affinity for alpha1-containing subunits are most useful use as hypnotics- at least when it comes to the various variations on the BZD site. Then there are compounds which bind to the Barbiturate site, the propofol site, etc. There's no shortage of unique binding sites. It's possible that some of these will eventually be recognized as parts of a whole- like a tic-tac-toe board where you've put your antagonist X down, my agonist O may fit fine right below it and still be on the same board. Zolpidem and it's analogues are actually believe to be able to bind in two wholly different modes.
To be entirely honest, if I were a research chemical vendor who wanted to make serious money without risking jail time, I'd be sure to start researching new- and old- GABAergic CNS depressants. Perhaps some of what's held them back is the risk of death in overdose. It's surely no coincidence that the two classes of RC that really took off (cannabinoids and stimulants) were the ones least likely to kill someone in an overdose. Phenazepam, Etizolam and 2-Methyl-2-Butanol have surely started to appear, but hardly like 'bath salts' and 'herbal incense.' Until someone starts selling a 2M2B beverage you're not going to see these in your local gas station. O-desmethyltramadol was the only opioid to really show up, and right off the bat people died. No surprises there.
I'll be posting the structures and information about many GABAergic compounds with references. I'll try to find some bioassays, but many won't have any and those that do will come from really old literature.
Starting with one that I haven't even read about yet, but certainly looks promising. Basic structure, and general anaesthetic generally means good things for those of us who want to sleep- though I wouldn't consider an anaesthetic dose!
Design, Synthesis, and Evaluation of Analogues of 3,3,3-Trifluoro-2-Hydroxy-2-Phenyl-Propionamide as Orally Available General Anesthetics
Indrani Choudhury-Mukherjee, Hilary A. Schenck, Sylvia Cechova, Thomas N. Pajewski J. Med. Chem., 2003, 46 (12), pp 2494–2501
DOI: 10.1021/jm020546r
We have recently discovered a novel class of compounds that have oral general anesthetic activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure. Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds. Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a putative mechanism. Liposomal partitioning studies using 19F NMR reveal that the aromatic region partitions into the core of the lipid. This partitioning correlated with general anesthetic activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM and slightly enhanced GABAA current in hippocampal neurons at 10 μM. Altogether, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).
It looks like it'd be rapidly metabolized, to me, but I'm no expert. Not the most potent drug, though.
Then you have compounds like the ones mentioned below. This is another paper I haven't read, but I have read the patent. This paper was paid for by Pfizer, however, though I don't believe these were ever taken to human studies and may have only gotten to this basic stage. There are also a few selected passages from the patent below (in NSFW boxes to shorten the post up a bit).
J Med Chem. 1989 Feb;32(2):437-44.
A novel class of "GABAergic" agents: 1-aryl-3-(aminoalkylidene)oxindoles.
Sarges R, Howard HR, Koe BK, Weissman A.
Abstract
Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dimethylamino)-ethylidene and N-methyl-2-pyrrolidinylidene side chains. The precise mechanism of action of these agents is unclear at this time; however, they are not GABA mimics and they do not affect GABA levels. Like other GABAergic agents, these compounds are potent enhancers of benzodiazepine binding and they antagonize cyclic GMP elevations induced by isoniazid. Compounds from this series may therefore have potential therapeutic utility as anticonvulsants or anxiolytics.
PMID: 2536440 [PubMed - indexed for MEDLINE]
Patent No. 4977178
Method of treating anxiety and depression with 1-phenyl-2(1H,3H)-indolone psycho-therapeutic agents
July 19, 1989 Inventors: Howard, Jr. Sarges; Reinhard Assignee: Pfizer Inc.
Certain novel, 1-phenyl-3-[aminoalkylidene or di(loweralkyl)aminoalkylidene]-2(1H, 3H)-indolones, specifically substituted on phenyl with at least one alkyl, alkoxy, alkylthio, chloro, fluoro or trifluoromethyl group, are potent gabaergic agents,valuable in the treatment of schizophrenia per se, as well as in reversing or avoiding side effect of oral-facial dyskinesia (tardive dyskinesia), commonly seen in schizophrenic individuals under present or past treatment with a neuroleptic agent. Thepresent invention encompasses these novel gabaergic agents, together with pharmaceutical compositions thereof, and use thereof in treating schizophrenia or reversing the side effects of a previously or concurrently administered neuroleptic agent. Mostof these compounds also have valuable anxiolytic activity, as detailed below.
More broadly, the present invention encompasses variously substituted 1-phenyl-3-[aminoalkylidene-, lower alkylaminoalkylidene- and di(loweralkyl)aminoalkylidene]-2(1H,3H)-indolones (some of which are known compounds), novel1-phenyl-3-(piperidino-, pyrrolidino-, morpholino- or imidazolo- alkylidene)-2(1H, 3H)-indolones and novel 1-phenyl-3-(2-pyrrolidinylidene, 2piperidinylidene, or 2-perhydroazepinylidene, optionally substituted on nitrogen with lower alkyl, phenyl orbenzyl)-2(1H,3H)-indolones. These three classes of compounds are anxiolytic agents, valuable in the treatment of hyperanxious individuals. The present invention is thus also directed to the above two novel classes of compounds and pharmaceuticalcompositions thereof, and to the use of all three classes of compounds in the treatment of anxiety in hyperanxious individuals.
Belgian Patent No. 849,626 broadly discloses compounds of the formula ##STR1## which include m as 1, 2 or 3 and R.sup.a and R.sup.b each as H, OH, lower alkyl, lower alkoxy, F, Cl, Br, NO.sub.2, NH.sub.2 or C.sub.6 H.sub.5 CH.sub.2.
These compounds are not disclosed as having pharmaceutical utility per se, but rather are indicated to be chemical intermediates. The only compounds of this class isolated and characterized are the two compounds wherein R.sup.a =H and R.sup.b =3-methoxy; and wherein R.sup.a =R.sup.b= H. The latter compound, like at least two dozen other compounds of this class, does not possess MPA (3mercaptopropionic acid) induced convulsion inhibitory activity ("gabaergic" activity). However, from among themany thousands of possible compounds defined by the Belgian patent, we have surprisingly found that a few, defined by the formula (I) below have gabaergic activity and so are useful in the treatment of schizophrenic individuals.
this compound is described below
NSFW:
The clinical utility of the novel compounds of the present invention in the treatment of individuals suffering from schizophrenia is reflected by their potent gabaergic activity. Gabaergic activity refers to the gamma-aminobutyric acid likeactivity of these compounds in inhibiting convulsions induced by 3mercaptopropionic acid in an animal model (see for example Roberts and Taberner, Brit. J. Pharmacol. 61:476P, 1977; Adcock and Taberner, Biochem. Pharmacol. 27:246; 1978). Subjects inthe present test were Charles-River male mice, Swiss CD strain, 17-21 g., fasted for 18 hours prior to testing. Compounds were administered subcutaneously or orally in a vehicle consisting of 5% ethanol, 5% emulphor 620 and 90% saline, which vehiclealone served as a control treatment. Compounds were tested on a 0.5.times.log .sub.10 dosage continuum, if active, to achieve data for determination of an ED.sub.50 value. Solution concentrations were varied at different doses to provide a constantinjection volume of 10 ml/kg. The grouped mice were treated with test compounds, and, 1 hour later with 3-mercaptopropionic acid (MPA), 32 mg/kg, intraperitoneally, after which they were observed continuously for 10 minutes. In untreated mice this MPAchallenge causes clonic convulsions within 4 minutes of treatment. Protection against MPA convulsions in a given mouse was said to occur if no convulsions occurred during the 10 minute test period. In this test, compounds of the formula (I) showedpotent activity. For example, subcutaneous ED.sub.50 H values ranged from 6.6 mg/kg for 1-(3-fluoro-4-methoxy-phenyl)-3-(dimethylaminomethylene)-2(1H,3H)-indolone to about 56 mg/kg for the otherwise corresponding 1(4-methylphenyl) and1-(4-methylthiophenyl) analogs. 1-Phenyl-3-(dimethylaminomethylene)-2(1H,3H)-indolone and an extensive number of analogous compounds showed no activity in this test, even at 100 mg/kg. Only a very few compounds of the formula (II) demonstrate suchactivity, e.g., 1-(3-fluoro-4-methoxyphenyl)-3(2-pyrrolidinylidene)-2(1H,3H)-indolone; the N-methyl analog thereof; and, in particular, 1-(4-methoxy-phenyl)-3-(1-methyl-2-pyrrolidinylidene)-2(1H,3H) indolone which shows an ED .sub.50 of 3.2-5.6- mg/kgsubcutaneously and 18-32 mg/kg orally.
The clinical utility of novel and known compounds of the present invention [formulae (II) and (III)] in the treatment of hyperanxiety is reflected in their potent in vivo effect on 3H-flunitrazepam (3H-FNP) . binding. This effect was measuredby the method of Koe and Weissman, J. Clin. Pharmacol. 21:397S, 1981. Groups of five mice, of the type described above, are injected subcutaneously with 320 micromole/kg of the test compound or vehicle 1 hour prior to an intravenous injection of 200microCi/kg .sup.3 H-FNP. Twenty minutes after the .sup.3 H-FNP injection, the mice were sacrificed by cervical dislocation, and the brains were removed and immediately frozen. Each brain was weighed quickly and homogenized in 40 volumes (w/v) ice-cold50 mM Tris HCl pH 7.7 buffer using a Brinkmann Polytron. Triplicate 1.0-ml samples were filtered through Whatman GF/B glass fiber filters under vacuum and washed with two 5 ml aliquots of the ice-cold buffer. The bound .sup.3 H-FNP was measured byadding the filters to vials containing 10 ml. Aquasol-2 and counting the radioactivity. Bound .sup.3 H-FNP for drugtreated mice was calculated as percentage of bound .sup.3 H-FNP for vehicle-treated mice. In this test, compounds of the formula (II) or(III) exhibit enhancement in .sup.3 H-FNP binding, for example, ranging from 126 % for 1-(3-chlorophenyl)-3-(moropholinomethylene)2(1,3H)-indolone and 1-(3-cyanophenyl)-3-(1-methyl-2-pyrrolidinylidene)-2(1H,3H)-indolone to greater than 250% for the mosthighly active compounds such as 1(3-chloro-4-methoxyphenyl)-3-(dimethylaminomethylene)2(1,3H)-indolone and 1-(3-fluoro-4-methoxy)-3-(1- methyl-2-pyrrolidinylidene)-2(1H,3H)-indolone.
I'm going to end this here before I go over the character limit, and I'll add more to this later.
Hmmm, when I get back from job training I'll have to add some neurosteroid info. Can't say I like the baiting for vendors though, but the intellectual masturbation is too tempting!
Can't sleep and happened to see this. I don't think vendors will be particularly interested in these. There are so many of these available with a quick view through Wikipedia that have never appeared even though for various reasons they'd make better RC's.
I'm planning on following each new collection of unique and unusual ligands with a post about the receptor itself. That's what I worked on this evening after this first post, and I'll have it up by tomorrow afternoon.
That slutty, slutty receptor, accepting allosteric modulation from all sorts of types of compounds! Do you have any further speculation about likely future differentiation of receptor sub-types or discovery of linkage between receptor subtype and subjective effects?
Is GABAA the optimal target tough? the benzo with that 2 hour half life (forgot the name) causes dependency while GHB (simular half life wich acts on GABAB) doesnt cause any physical addiction with long term use, indicating GABAB receptors are more forgiving when activated on a daily basis for a short period of time).
not saying GHB is ideal as increased REM sleep particurally benefits narcoleptics but may increase depression in other individuals, that said its highly addictive but the addition of naltrexone seems succesfull when using it therapeutically in alcoholics.
Abstract
A set of sulfamides designed, synthesized and evaluated against maximal electroshock seizure (MES) and pentilenetetrazol (PTZ) tests with promising results, were tested for their affinity for the benzodiazepine binding site of the GABA(A) receptor. The most active compounds, N,N'-dicyclohexylsulfamide (7) and N,N'-diphenethylsulfamide (10), competitively inhibited the binding of [(3)H]-flunitrazepam to the benzodiazepine binding site with K(i)±SEM values of 27.7±4.5μM (n=3) and 6.0±1.2μM (n=3), respectively. The behavioral actions of these sulfamides, i.p. administered in mice, were examined in the plus-maze, hole-board and locomotor activity assays. Compound 7 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the hole-board test (at 1 and 3mg/kg) and the plus-maze assay (at 1 and 3mg/kg). Compound 10 evidenced anxiolytic activity in the plus-maze and the hole-board tests at 1mg/kg. Locomotor activity of mice was not modified by compound 7 or 10 at the doses tested. Flumazenil, a non selective benzodiazepine binding site antagonist, was able to completely reverse the anxiolytic-like effects of these sulfamides, proving that the GABA(A) receptor is implicated in this action. Anxiety represents a major problem for people with epilepsy. The use of anxiolytic and anticonvulsant sulfamides would be beneficial to individuals who suffer from both disorders.
Abstract
A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl-carbamate (38 ) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED(50) = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38 ) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED(50) = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy-safety profile and, consequently, are promising candidates for development as new antiepileptics.
Ethyl carbamate (urethane) is often used as a general anesthetic for lab animals, but can't be used in humans because of carcinogenicity. I'm not sure whether the other carbamate derivatives would cause cancer, too. Meprobamate certainly doesn't. The most potent simple carbamate was found to be phenethyl carbamate in this paper.
(note: I'm going to swap the order of these posts around eventually so they flow better but for now I'll leave them as they are.)
The GABA A receptor is somewhat unique when compared to many other receptors associated with psychoactive compounds in that it's an ionotropic receptor. The only other ionotropic receptor targeted by recreational drugs that comes to mind is the glutamate receptor, but that's a completely different kind of incredibly complex- requiring TWO agonists to be activated. Both of these receptors are all the proof I need that there wasn't a divine watchmaker behind our creation. If there was a God designing us, I'm sure he could have come up with something less convoluted.
Ionotropic receptors are receptors which, when activated, allow a current of charged particles to pass. In the case of GABA receptors, the charged particles are Cl- ions. When GABA, or another agonist like muscimol or gaboxadol binds to the site the pore is opened and the Cl- particles may pass. This is an incredibly quick event, however, and the flow of Cl- particles is kept extremely well regulated. There are many different allosteric sites, however, and when a "positive allosteric modulator" (frequently referred to as an agonist, but this is incorrect usage) binds to the site it may cause a number of things to occur. When a benzodiazepine (BZD) site PAM binds, it causes the chloride channel to open more frequently. When a barbiturate-site PAM binds, however, it causes the chloride channel to remain open for a longer time, but slightly decreases the rate of pore opening. This is thought to be the result of a Barbiturate-mediated conformational change in the GABA binding site which inhibits the release of GABA from it's binding site. The slight decrease in pore opening rate may be caused by that same conformational change which may make binding at the agonist site more difficult. I should add here that neither BZD or BARB PAMs have any effect on chloride channel conductance in the absence of GABA. That's what makes these allosteric sites, of course- they don't have the ability to activate the receptor themselves, but they do have an important and sometimes dramatic effect on the activity of GABA (or whatever agonist is present).
To date, allosteric sites are identified for at least the following classes of ligands, BZDs, barbiturates, ethanol, neuroactive steroids, picrotoxin, and maybe inhaled anaesthetics. Additionally, there may be some overlap of some in these sites, as is shown in the image below, but this isn't something well defined and is an area of active research.
When I was reading this I was reminded of a past conversation we had here about anaesthetic gases. We had talked about inhaled anaesthetics like diethyl ether and the halogenated ethers, and how actually all inhaled gases will produce anaesthetic effects if they're inhaled at the right pressure. That's actually not true, though. There are known antagonists of their effects, like Helium and perhaps more relevantly, Flurothyl. This study talks about the binding site in relatively limited, but interestingly useful detail.
NSFW:
Anesth Analg. 1999 Jun;88 (6):1395-400.
Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart.
Eger EI 2nd, Halsey MJ, Harris RA, Koblin DD, Pohorille A, Sewell JC, Sonner JM, Trudell JR.
Source
Department of Anesthesia and Perioperative Medicine, University of California, San Francisco 94143-0464, USA. [email protected]
Abstract
All series of volatile and gaseous compounds contain members that can produce anesthesia, as defined by the minimum alveolar anesthetic concentration (MAC) required to produce immobility in response to a noxious stimulus. For unhalogenated n-alkanes, cycloalkanes, aromatic compounds, and n-alkanols, potency (1 MAC) increases by two-to threefold with each carbon addition in the series (e.g., ethanol is twice as potent as methanol). Total fluorination (perfluorination) of n-alkanes essentially eliminates anesthetic potency: only CF4 is anesthetic (MAC = 66.5 atm), which indicates that fluorine atoms do not directly influence sites of anesthetic action. Fluorine may enhance the anesthetic action of other moieties, such as the hydrogen atom in CHF3 (MAC = 1.60 atm), but, consistent with the notion that the fluorine atoms do not directly influence sites of anesthetic action, adding -(CF2)n moieties does not further increase potency (e.g., CHF2-CF3 MAC = 1.51 atm). Similarly, adding -(CF2)n moieties to perfluorinated alkanols (CH2OH-[CF2]nF) does not increase potency. However, adding a second terminal hydrogen atom (e.g., CHF2-CHF2 or CH2OH-CHF2) produces series in which the addition of each -CF2- "spacer" in the middle of the molecule increases potency two- to threefold, as in each unhalogenated series. This parallel stops at four or five carbon atom chain lengths. Further increases in chain length (i.e., to CHF2[CF2]4CHF2 or CHF2[CF2]5CH2OH) decrease or abolish potency (i.e., a discontinuity arises). This leads to our hypothesis that the anesthetic moieties (-CHF2 and -CH2OH) interact with two distinct, spatially separate, sites. Both sites must be influenced concurrently to produce a maximal anesthetic (immobility) effect. We propose that the maximal potency (i.e., for CHF2[CF2]2CHF2 and CHF2[CF2]3CH2OH) results when the spacing between the anesthetic moieties most closely matches the distance between the two sites of action. This reasoning suggests that a distance equivalent to a four or five carbon atom chain, approximately 5 A, separates the two sites. IMPLICATIONS: Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.
PMID: 10357351
J Pharmacol Exp Ther. 2010 Dec;335(3):600-6. Epub 2010 Sep 8.
A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics.
McCracken ML, Borghese CM, Trudell JR, Harris RA.
Source
Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, Texas 78712, USA.
Abstract
NSFW:
Alcohols and inhaled anesthetics enhance the function of GABA(A) receptors containing α, β, and γ subunits. Molecular analysis has focused on the role of the α subunits; however, there is evidence that the β subunits may also be important. The goal of our study was to determine whether Asn265, which is homologous to the site implicated in the α subunit (Ser270), contributes to an alcohol and volatile anesthetic binding site in the GABA(A) receptor β(2) subunit. We substituted cysteine for Asn265 and exposed the mutant to the sulfhydryl-specific reagent octyl methanethiosulfonate (OMTS). We used two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes and found that, after OMTS application, GABA-induced currents were irreversibly potentiated in mutant α(1)β(2)(N265C)γ(2S) receptors [but not α(1)β(2)(I264C)γ(2S)], presumably because of the covalent linking of octanethiol to the thiol group in the substituted cysteine. It is noteworthy that this effect was blocked when OMTS was applied in the presence of octanol. We found that potentiation by butanol, octanol, or isoflurane in the N265C mutant was nearly abolished after the application of OMTS, suggesting that an alcohol and volatile anesthetic binding site at position 265 of the β(2) subunit was irreversibly occupied by octanethiol and consequently prevented butanol or isoflurane from binding and producing their effects. OMTS did not affect modulation or direct activation by pentobarbital, but there was a partial reduction of allosteric modulation by flunitrazepam and alphaxalone in mutant α(1)β(2)(N265C)γ(2S) receptors after OMTS was applied. Our findings provide evidence that Asn265 may contribute to an alcohol and anesthetic binding site.
FASEB J. 1995 Nov;9(14):1454-62.
Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition.
Harris RA, Mihic SJ, Dildy-Mayfield JE, Machu TK.
NSFW:
Abstract
Molecular cloning of cDNAs coding for ligand-gated ion channel subunits makes it possible to study the pharmacology of recombinant receptors with defined subunit compositions. Many laboratories have used these techniques recently to study actions of agents that produce general anesthesia. We review the effects of volatile and intravenous anesthetics on recombinant GABAA, glycine, AMPA, kainate, NMDA, and 5HT3 receptors. Evidence for and against specific ligand-gated ion channel subunits as targets responsible for anesthesia or the side effects of anesthetic agents is discussed for each type of receptor. Subunit specific actions of some of the agents suggest that construction and testing of certain chimeric receptor subunits may be useful for defining the amino acid sequences responsible for anesthetic actions.
PMID: 7589987
Anesthesiology. 2000 Oct;93(4):1095-101.
Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol.
Yamakura T, Harris RA.
Abstract
NSFW:
BACKGROUND:
Ligand-gated ion channels are considered to be potential general anesthetic targets. Although most general anesthetics potentiate the function of gamma-aminobutyric acid receptor type A (GABAA), the gaseous anesthetics nitrous oxide and xenon are reported to have little effect on GABAA receptors but inhibit N-methyl-d-aspartate (NMDA) receptors. To define the spectrum of effects of nitrous oxide and xenon on receptors thought to be important in anesthesia, the authors tested these anesthetics on a variety of recombinant brain receptors.
METHODS:
The glycine, GABAA, GABA receptor type C (GABAC), NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, 5-hydroxytryptamine3 (5-HT3), and nicotinic acetylcholine (nACh) receptors were expressed in Xenopus oocytes and effects of nitrous oxide and xenon, and as equipotent concentrations of isoflurane and ethanol, were studied using the two-electrode voltage clamp.
RESULTS:
Nitrous oxide (0.58 atmosphere [atm]) and xenon (0.46 atm) exhibited similar effects on various receptors. Glycine and GABAA receptors were potentiated by gaseous anesthetics much less than by isoflurane, whereas nitrous oxide inhibited GABAC receptors. Glutamate receptors were inhibited by gaseous anesthetics more markedly than by isoflurane, but less than by ethanol. NMDA receptors were the most sensitive among glutamate receptors and were inhibited by nitrous oxide by 31%. 5-HT3 receptors were slightly inhibited by nitrous oxide. The nACh receptors were inhibited by gaseous and volatile anesthetics, but ethanol potentiated them. The sensitivity was different between alpha4beta2 and alpha4beta4 nACh receptors; alpha4beta2 receptors were inhibited by nitrous oxide by 39%, whereas alpha4beta4 receptors were inhibited by 7%. The inhibition of NMDA and nACh receptors by nitrous oxide was noncompetitive and was slightly different depending on membrane potentials for NMDA receptors, but not for nACh receptors.
CONCLUSIONS:
Nitrous oxide and xenon displayed a similar spectrum of receptor actions, but this spectrum is distinct from that of isoflurane or ethanol. These results suggest that NMDA receptors and nACh receptors composed of beta2 subunits are likely targets for nitrous oxide and xenon
A particularly interesting study...
J Biol Chem. 2010 Mar 19;285(12):8615-20. Epub 2010 Jan 18.
Numerous classes of general anesthetics inhibit etomidate binding to gamma-aminobutyric acid type A (GABAA) receptors.
Li GD, Chiara DC, Cohen JB, Olsen RW.
Abstract
NSFW:
Enhancement of gamma-aminobutyric acid type A receptor (GABA(A)R)-mediated inhibition is a property of most general anesthetics and a candidate for a molecular mechanism of anesthesia. Intravenous anesthetics, including etomidate, propofol, barbiturates, and neuroactive steroids, as well as volatile anesthetics and long-chain alcohols, all enhance GABA(A)R function at anesthetic concentrations. The implied existence of a receptor site for anesthetics on the GABA(A)R protein was supported by identification, using photoaffinity labeling, of a binding site for etomidate within the GABA(A)R transmembrane domain at the beta-alpha subunit interface; the etomidate analog [(3)H]azietomidate photolabeled in a pharmacologically specific manner two amino acids, alpha1Met-236 in the M1 helix and betaMet-286 in the M3 helix (Li, G. D., Chiara, D. C., Sawyer, G. W., Husain, S. S., Olsen, R. W., and Cohen, J. B. (2006) J. Neurosci. 26, 11599-11605). Here, we use [(3)H]azietomidate photolabeling of bovine brain GABA(A)Rs to determine whether other structural classes of anesthetics interact with the etomidate binding site. Photolabeling was inhibited by anesthetic concentrations of propofol, barbiturates, and the volatile agent isoflurane, at low millimolar concentrations, but not by octanol or ethanol. Inhibition by barbiturates, which was pharmacologically specific and stereospecific, and by propofol was only partial, consistent with allosteric interactions, whereas isoflurane inhibition was nearly complete, apparently competitive. Protein sequencing showed that propofol inhibited to the same extent the photolabeling of alpha1Met-236 and betaMet-286. These results indicate that several classes of general anesthetics modulate etomidate binding to the GABA(A)R: isoflurane binds directly to the site with millimolar affinity, whereas propofol and barbiturates inhibit binding but do not bind in a mutually exclusive manner with etomidate.
PMID: 20083606
i have used l-lysine with benzodiazepenes, and there was much more profound effect.
and personally (i have tested with three benzos, nitrazepam, alprazolam and bromazepam) the most enhanced was nitrazepam.
10mg of nitrazepam felt as if i'd been hit in the face with a sledgehammer type sedation along with 500mg of l-lysine in the morning and 500mg l-lysine 1 hour prior to taking it.
the sedation on alprazolam was also increased but not to the same level, but definately sedated me much more than usual at a 1.5mg dose.
the bromazepam didn't seem effected by it...
i don't believe for a second it enhances GABA binding - i think there is something else at play here.
a friend told me he saw on a legal forum people talking about bringing atagablin to market dont know if pregablin binds to GABA A but i know it does to calcium channels I would like to know more on other novel GABA-A receptor compounds though
I agree with the first statement and wonder how the hell you came to the second. GHB is remarkably physically addictive. Look at the countless Erowid and Bluelight reports. Many can't go five hours sleeping without having to re-dose. Any drug with GABAergic action can be physically addictive, even GABA-B (check out Phenibut addiction).
I feel like i play nanny on this site a little too much but I still have to say this: Though you, Hammilton, are obviously one of the most knowledgeable individuals to frequent Bluelight, you are not a doctor, correct? Even if you were a doctor, medical professionals don't actually prescribe drugs based on pharmacology so much as on statistical efficacy within great populations once a drugs use becomes widespread. Hell, many psychiatrists aren't even aware of many drugs pharmacological mechanisms. And people will be particularly bias toward things such as reward and expectation when self-medicating; tis a very dangerous game to play. Maybe you should have opened the thread up a little in asking for alternative methods to sleep. That way people could offer activities in addition to more benign drugs rather than referring you to some obscure GABAergic compound; it doesn't scare you to ask on the internet for recommendations regarding basically untested substances which no doubt are extremely dangerous so that you can self-medicate? Fuck.
I mean you're limiting the benevolence of replies at least by restricting this to GABAergics, which almost all disturb sleep structure and are impossible to get off of after long-term use, not to mention damage the brain. Just saying. Don't flame this post. I assume you're aware of studies such as this: http://bmjopen.bmj.com/content/2/1/e000850.full
My answer to the original question would be to use Temazepam since it has the advantage of being one of the most widely used, oldest, and sleep-structure-safe GABAergic drugs indicated for sleep; but its been shown at least once to cause organic brain damage after long-term use. I can't find this study quickly now but I can find it if you need the source.
Honestly I'd also look into high-dose Depakote. Barely addictive and GABAergic. Like a non-euphoric alcohol relative to sedation.
