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	All 19 posts		Subject: New GHB analogs, any thoughts?		Please login to post		Down

		Zha77 (Stranger) 05-20-04 09:59 No 508402				New GHB analogs, any thoughts?
						Just came across this drug being marketing as a supplement called phenibut. The similarities to GHB seem striking. Has anyone tried this? I will let you know how it is in a few days.
		M3Psych (Hive Bee) 05-20-04 16:02 No 508449				It looks like phenyl-GABA to me, probably...
						It looks like phenyl-GABA to me, probably nothing special.
		ApprenticeCook (Hive Bee) 05-20-04 17:04 No 508456				try it as is, but not expecting anything, try...
						try it as is, but not expecting anything, try and process it to phenyl-ghb? may kill you in trials but hey, thats science. Ph-GABA --> Ph-GHB??? well if it is something special be sure to tell us all. Its just my opinion, but no-one listens to me anyway, and rightly so...
		merbst (Hive Bee) 05-20-04 17:40 No 508465				I got 30g as part of my quest to find the most
						I got 30g as part of my quest to find the most effective legal sedative with the least side effects.  I find 1g to provide a relaxing feeling akin to a large dose of Kava. It goes by the names "3-phenyl-GABA", "beta-phenyl-GABA", and "phenibut". This thread has more information: http://www.dr-bob.org/babble/alter/20031104/msgs/278284.html As well as these threads: http://forums.1fast400.com/topic1649.html http://forums.1fast400.com/topic1518.html http://forum.avantlabs.com/index.php?act=ST&f=1&t=5631 http://forum.avantlabs.com/?s=6437db1c16491f379e3480ea382cd88e&act=ST&f=1&t=5631&st=60 Closely related are: Picamilon (N-nicotenoyl-GABA) and Baclofen I've also experimented with Calcium/Magnesium Butyrate (see my old thread) and GABA which both also have mild sedative effects.  See Post 487039 (merbst: "Butyric acid salts as GABA substrate!", General Discourse). In looking around on http://gb.espacenet.com I found a huge number of GABA analogues. Here are some of the ones I found more interesting: US2004058991 N-alkylated gaba compounds, processes for their preparation and their use as medicaments The present invention relates to N-alkylated GABA (Gamma-aminobutyric acid) compounds, to processes for their preparation, to their use in therapy and to pharmaceutical compositions containing them. More particularly these compounds are useful for treatment of disorders of the central and/or peripheral nervous system. Of particular interest is their potent anticonvulsant activity. Patent US6720339 Certain fused pyrrolecarboxamides; a new class of GABA brain receptor ligands Patent US6710190 3-heteroarylalkyl substituted gaba analogs Patent US6723735 Imidazo-pyridine derivatives as ligands for GABA receptors The present invention is directed to 3-phenylimidazol[4,5-b]pyridine derivatives, that are selective ligands for GABAA receptors. These compounds are useful in the treatment and prevention of disorders of the central nervous system, including anxiety and convulsions. Patent EP1404324 PRODRUGS OF GABA ANALOGS, COMPOSITIONS AND USES THEREOF The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using phannaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders Patent US2002198204 Certain fused pyrrolecarboxamides; a new class of GABA brain receptor Disclosed are compounds of the formula or the pharmaceutically acceptable non-toxic salts thereof wherein: W represents substituted or unsubstituted aryl or heteroaryl; T is hydrogen, halogen, hydroxyl, amino or alkyl; X is hydrogen, hydroxy, or lower alkyl; m is 0, 1, or 2; n is 0, 1, or 2; and R3 and R4 represent substituted or unsubstituted organic residues. These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
		Zha77 (Stranger) 05-21-04 00:39 No 508514				There are very few reports of this in English, (Rated as: good read)
						There are very few reports of this in English, and very few companies selling it. Although the reports are raving for a cheap and legal drug.  The similarties to PEA intrigue me most, almost like GHB with a semi-stimulating effect. It undoubtately falls under the Federal Analog act. Ever since Ashcroft raped hundreds of ghb users of thier civil rights, I have had no success finding a successful alternative, and the toxic fumes required for synthesis is not on option. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. Lapin I. Department of Clinical and Experimental Psychopharmacology, Bekhterev's Psychoneurological Institute, Bekhterev Street, 3, St. Petersburg, 193019, Russia. spbinstb@infopro.spb.su Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders. If any of you know russian, I imagine there is signifigant literature on it.
		ego (Stranger) 05-23-04 02:24 No 508908				Links
						Hi! Please post links (russian or english). What about beta-phenyl-GHB? Can I do it from phenibut with HNO2? Thanks!
		Antoncho (Official Hive Translator) 05-26-04 06:49 No 509686				Phenibut's inactive
						Phenibut has absolutely no recreational value (i've been using this substance for quite a while). It's a widely used substance in Russia and generally reports are the same: mostly nothing, beecomes noticeable only when the subject has some anxiety/fears etc. BTW, does an AWESOME job of reducing aftereffects of dopaminergic stimulants.
		scarmani (Hive Bee) 05-30-04 02:56 No 510235				Baclofen and Novel "GABAergics" (Rated as: good read)
						It seems that GABA-B and 5HT1-A receptors are targets for several drugs that are not as "recreational" [i.e., acutely intoxicating] as benzodiazepines, but may have useful or even pleasant anxiolytic and anti-addictive(?) properties.  Baclofen causes "mild sedative-like subjective effects, such as increases in feeling 'relaxed'" at 20 mg. The similarities between compounds such as Phenibut and PEA's may have to do with relationship between GABA and 5HT1 pathways.  Certainly, many PEA's and tryptamines have some affinity across the range of 5HT subtypes, which may contribute to their individually unique "flavors". For example, I vaguely recall that some 2-Me substituted tryptamines had significant affinity for 5HT1 receptors, and 2,a-DMT shows a sedative effect (http://www.erowid.org/library/books_online/tihkal/tihkal07.shtml).  There have been a lot of studies showing various 5HT1 receptor agonists to have antidepressant and anxiolytic behavioral profiles in animal models.  IMHO, 5HT1 agonists represent an interesting, possibly promising area for recreational drugs. A few other GABA-related compounds that look interesting from receptor binding studies are trans-4-Aminocrotonic acid (TACA) and 3-Aminopropyl(methyl)phosphinic acid, although I have no idea whether these small simple molecules would have general & pharmacological properties compatible with human recreational use. ----------------- . Effects of a single dose of baclofen on self-reported subjective effects and tobacco smoking Michael S. Cousins, Heather M. Stamat, Harriet de Wit Nicotine & Tobacco Research. 2001 May; 3(2):123-29. (http://www.streamload.com/scarmani/GABA/Effects_of_a_single_dose_of_baclofen_on_self-reported_subjective_effects_and_tobacco_smoking.pdf) DOI:10.1080/14622200123942: Abstract: Baclofen has been reported in uncontrolled clinical studies to reduce craving for abused drugs and reduce their rewarding effects. The objective of the present study was to measure the acute effects of a single dose of baclofen on cigarette smoking, craving for nicotine, cigarette taste, and smoking satisfaction. Tobacco smokers (n = 16) who were not trying to quit received baclofen (20 mg) or placebo after overnight abstinence during two laboratory sessions in a within-subjects design. We measured the subjective effects of baclofen on mood and self-reported ratings of craving for nicotine, and on the number of cigarettes smoked of the subjects' preferred brand during a 3-h ad libitum smoking period. Baclofen did not change the number of cigarettes smoked by the subjects nor did it change ratings of nicotine craving. However, baclofen altered the sensory properties of smoked cigarettes (e.g., increasing ratings of 'harsh' and decreasing ratings of 'like cigarette's effects'). It also produced mild sedative-like subjective effects, such as increases in feeling 'relaxed'. Thus, although baclofen did not reduce cigarette craving or smoking in the present study, it did produce some mood-altering effects and changes in sensory aspects of smoking that may facilitate smoking cessation. ----------------- http://www.sciencedaily.com/releases/2003/12/031217073535.htm. ----------------- GABAB receptors in 5-HT transporter- and 5-HT1A receptor-knock-out mice: further evidence of a transduction pathway shared with 5-HT1A receptors Mannoury la Cour C, Hanoun N, Melfort M, Hen R, Lesch KP, Hamon M, Lanfumey L. J Neurochem. 2004 May; 89(4):886-96. (http://www.streamload.com/scarmani/GABA/GABAB_receptors_in_5-HT_transporter-_and_5-HT1A_receptor-knock-out_mice_further_evidence_of_a_transduction_pathway_shared_with_5-HT1A_receptors.pdf) DOI:10.1111/j.1471-4159.2004.02367.x: Abstract: The functional properties of GABA-B receptors were examined in the dorsal raphe nucleus (DRN) and the hippocampus of knock-out mice devoid of the 5-HT transporter (5-HTT-/-) or the 5-HT1A receptor (5-HT1A-/-). Electrophysiological recordings in brain slices showed that the GABAB receptor agonist baclofen caused a lower hyperpolarization and neuronal firing inhibition of DRN 5-HT cells in 5-HTT-/- versus 5-HTT+/+ mice. In addition, [35S]GTP-gamma-S binding induced by GABAB receptor stimulation in the DRN was approximately 40% less in these mutants compared with wild-type mice. In contrast, GABAB receptors appeared functionally intact in the hippocampus of 5-HTT-/-, and in both this area and the DRN of 5-HT1A-knock-out mice. The unique functional changes of DRN GABAB receptors closely resembled those of 5-HT1A autoreceptors in 5-HTT-/- mice, further supporting the idea that both receptor types are coupled to a common pool of G-proteins in serotoninergic neurons. ----------------- . Behavioral characterization of the novel GABA-B receptor positive modulator GS39783 (N, N'- Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side-effects associated with baclofen or benzodiazepines. Cryan JF, Kelly PH, Chaperon F, Gentsch C, Mombereau C, Lingenhoehl K, Froestl W, Bettler B, Kaupmann K, Spooren WP. J Pharmacol Exp Ther. 2004 Apr 27 DOI:10.1124/jpet.104.066753: Abstract: The role of gamma-aminobuytric acid (B) (GABAB) receptors in various behavioural processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioural paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety the role of GABA-B receptors in these disorders is largely unclear. We recently identified GS39783 as a selective allosteric positive modulator at GABAB receptors. The aim of the present studies was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition and anxiety. The following tests were included; locomotor activity in rats and mice, rotarod and traction tests (including determinations of core-temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature or narcosis. Most interestingly GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABA-B receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side-effect profile to both baclofen and benzodiazepines. stop, drop & roll
		bouncer (Stranger) 06-18-04 01:39 No 514032				Why not GHB or even 1.4 BDO ??
						Is the whole board from US? I seem to find thread every week saying "GHB-like substance is there". For all the fellas outside the US - GHB/GBL/BDO is REALLY EASY to get acccess to. And in some places (where I live for example ;-) it is perfectly legal substance. Take care yall
		aragorn (Hive Bee) 06-18-04 07:19 No 514084				@bouncer
						no the hive has members from all over the globe but I assume that most members are US/EU bees. While the US GHB, G-analog and precursor control seems to be the severest all countries has adapted their drug laws to UN recommendations. Sure in some parts of the world GBL is still obtainable but why don´t look for promising GHB analogs or new synths? I strongly doubt that GHB is perfectly legal in any Western country, two years ago maybe but today the situation is no longer that good. Hive bee por vida!
		Marcilla (Hive Bee) 06-25-04 11:54 No 515328				Why GBL, you ask?
						Just to answer that question, despite it's legal status in the US as a List 1 chemical, GBL is still manufactured and transported in substancial quantities. Therefore, once the legal hurdles are overcome, the quantities of scale make obtaining GBL far more economical than starting somewhere else (such as with GABA). I'm sure there are plenty of people who look at that synth, calculate the quantity they need and then say, "I wonder what it would take to open my own nail salon/beauty supply/floor refinishing bidness?" And I have yet to read a report of a similar molecule with the same level of psychoactivity. As I recall, Shulgin reports on a GHB-like quality to one of the PEA, but I have read of no further research in this area. Were samples made available, I *might* bee able to find human subjects for bioassay [g]. XXOO, Marcilla Ask your doctor if a free sample of prescription Xyrem is right for you.
		Fastandbulbous (Hive Bee) 06-26-04 22:55 No 515624				Another GABA agonist
						According to the Tocris catalogue, trans-4-aminocrotonic acid (4-amino-2-butenoic acid) is a potent GABA-A agonist. It's also a GABA-C agonist and an inhibitor of GABA reuptake. All in all, it sounds like it might be potentially useful. It also has an entry for trans-4-hydroxycrotonic acid, where it states that it has a higher affinity for the receptor than GHB, but very little info other than that For those interested, the Tocris catalogue no is 0181. The entry also gives journal references regarding activity. That is right, the Mascara Snake: Fast and bulbous
		Rhodium (Chief Bee) 06-29-04 16:02 No 516305				GABA-B (Rated as: good read)
						Yes, but the interesting action of GHB is that it is a selective GABAB agonist, which is very uncommon. GABAB agonists such as baclofen still has a greater affinity for GABAA than GABAB. This fact also makes GABAB positive modulators interesting, as they are to GABAB what the benzodiazepines are to GABAA. Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF., Neuropsychopharmacology 29(6), 1050-62 (2004) Abstract Although there is much evidence for a role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA(B) receptors in behavioral processes related to these disorders has not yet been fully established. GABA(B) receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA(B(1)) and GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack functional GABA(B) receptors, and pharmacological tools we assessed the role of GABA(B) receptors in anxiety- and antidepressant-related behaviors. In the light-dark box, GABA(B(1)) -/- mice were more anxious than their wild-type littermates (less time spent in the light; reduced number of transitions). GABA(B(1)) -/- mice were also more anxious in the staircase test. Conversely, acute and chronic treatment with GS39783, a novel GABA(B) receptor positive modulator, decreased anxiety in the light-dark box and elevated zero maze tests for anxiety. On the other hand, GABA(B(1)) -/- mice had decreased immobility (antidepressant-like behavior) in the forced swim test (FST). These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA(B) receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the generation of novel antidepressants. The Hive - Clandestine Chemists Without Borders
		Rhodium (Chief Bee) 09-19-04 01:59 No 532073				Phenibut Science - By David Tolson (Rated as: good read)
						Phenibut Science By David Tolson Introduction Phenibut (beta-phenyl- gamma-aminobutyric acid, also spelled fenibut, originally known as phenigamma) is a derivative of the neurotransmitter GABA that crosses the blood-brain barrier [1]. It was developed in Russia, and there it has been used clinically since the 1960's for a range of purposes. Phenibut has both nootropic and anxiolytic (anxiety-reducing) properties, and it is commonly compared to diazepam (Valium), baclofen, and piracetam, and it has similarities to and differences from all of these substances. Structurally, phenibut is similar to GABA, baclofen (p-Cl-phenibut), and beta-phenylethylamine (PEA). GABA is the primary inhibitory neurotransmitter in the brain. The addition of the phenyl ring to GABA allows the compound to more easily cross the blood-brain barrier, but also changes its activity profile [1-2]. Baclofen is a drug commonly used in studies on GABA(B) receptors, and also clinically used to treat severe spasticity of cerebral origin [3]. PEA is a naturally occuring biogenic amine which is similar in structure to amphetamine, and like amphetamine, it is a stimulant that causes the release of dopamine, and also promotes anxiety in high enough amounts. Phenibut is a GABA receptor agonist and also causes the release of GABA. Similar to baclofen, phenibut is an agonist at GABA(B) receptors, although it does have some effect on GABA(A) receptors as well [2]. It is possible that phenibut has a higher activity at central GABA(B) receptors than peripheral ones [4]. The role of the GABA(B) receptor is not well-established, although research in the last seven years has significantly increased our understanding of this receptor. The most well-established role of GABA(B) receptors is inhibition of the release of some neurotransmitters, and it may also serve as a negative feedback mechanism for GABA release [5-6]. Because of the structural similarity to PEA, phenibut may share some similarities and differences with it. When phenibut is administered along with PEA, it antagonizes many of its effects, such as promotion of anxiety, promotion of seizures, and hyperthermia. This has lead some to postulate that antagonism of PEA, rather than the GABA-mimetic activity, may be the important mechanism of action for tha anxiolytic effect of phenibut [2, 7]. Phenibut also increases dopamine levels, and it has been postulated that the structural similarity to PEA may play a role in this effect [2]. There is one report in the literature of serotonergic effects of phenibut [8], but it does not look as though this has been followed up on. Effects of phenibut Anxiety reduction. Phenibut is effective in many animal models of anxiety, although there is often dependence on study conditions. In cats classified as "anxious" or "passive," phenibut reduced the fear response and increased aggression in a confrontational situation, while it had no effect on aggressive cats. In normal cats, it lead to "positive emotional symptoms" [2]. In mice, phenibut increased social behavior [9]. In rats, phenibut decreased some of the physiological responses to stress, including the elevation of glucocorticoid levels [10]. Phenibut has also been reported to decrease the fear response caused by electrical stimulation and counteract the anxiogenic effect of the beta-carboline DMCM [2, 11]. Studies in rats examined the behavioral properties of phenibut when it was administered locally into different parts of the brain, and it usually lead to a reduction of anxiety in one or more models [12-16]. The results of animal models don't always pan out in the real world, however, phenibut has a mechanism of action similar to that of many drugs which are known to reduce anxiety in humans. Animal studies have compared the profile of phenibut to diazepam (Valium), which has pronounced anxiolytic properties, and piracetam, which has weak anxiolytic properties. One study found phenibut had a tranquilizing effect similar to, but weaker than diazepam. It also caused sedation and muscle relaxation (whereas piracetam did not), but again these effects were weaker than those caused by diazepam [2]. In Russia, phenibut is commonly used to treat many neuroses, including post-traumic stress disorder, stuttering, and insomnia. In double blind placebo-controlled studies, phenibut has reportedly been found to improve intellectual function, improve physical strength, and reduce fatigue in neurotic and psychotic patients [2]. Nootropic effects. Although phenibut does not meet all the requirements of a nootropic, it does have many similarities to piracetam. In mice, phenibut causes significant improvement on the passive avoidance test [2]. In this test of memory, animals are put in an undesirable area (such as a lighting situation or height from the floor that that species dislikes), and then given a negative stimulus (such as a shock) when they exit that area. Their ability to stay in the original area reflects how well they remember that if they exit it, they will receive the undesirable stimulus. Phenibut also improves performance on the swimming and rotarod tests and antagonizes the amnestic effect of chloramphenicol [2]. It also has an antihypoxic effect, a trait commonly seen among nootropics [17]. However, in one study, phenibut was ineffective in the water maze and shuttle box tests, while piracetam was [18]. Other research supports the idea that phenibut has nootropic activity similar to that of piracetam, but not as strong [19]. Nootropic activity has also been reported in humans [2], but it was not specified whether these were healthy adult humans, and they were probably elderly or psychiatric patients. Another trait phenibut shares with nootropics is neuroprotection. Multiple animal studies have indicated that phenibut administration increases resistance to the detrimental effects of edema on mitochondria and energy production in the brain [20-22]. Phenibut also normalizes brain energy metabolism changes caused by chronic stress [23]. It was found to prevent changes in plasma electrolytes caused by cerebral injury [24]. Phenibut also protects dopaminergic neurons, and improved the condition of patients being treated with antiparkinsonic drugs [25]. Other effects. Phenibut has anticonvulsant activity against some drugs or conditions, but not others. It also potentiates the action of some other anticonvulsant drugs, and has been used to treat patients with epilepsy [2]. Phenibut has been reported to reduce motion sickness, and used in the treatment of alcohol and morphine withdrawal [2, 26]. One study indicated that phenibut increased resistance to heat stress and improved working capacity in humans [27]. Some studies indicate that phenibut has anti-arrhythmic properties in humans [28-29]. It also has other cardioprotective properties [30-31]. Finally, phenibut showed promise in experimental models of gastric lesions [32-33]. Side effects and suggested use Phenibut has low acute toxicity. Reported LD50s (dose required to kill 50% of laboratory animals) are 900 mg/kg i.p. in mice, 700 mg/kg i.p. in rats, and 1000 mg/kg in rats (method of administration not given) [2, 34]. Chronic administration of 50 mg/kg did not have teratogenic effects in rats [34]. In clinical studies, no signs of toxicity have been reported, and side effects are few. Some report drowsiness, but this effect is not nearly as likely or severe as with benzodiazepines [2]. One should be aware of the potential for drug interactions when taking phenibut. In many cases, it will decrease the threshold dose and potentiate certain actions of a drug. It amplifies some of the effects of anesthetics (ether, chloral hydrate, and barbiturates), diazepam, alcohol, and morphine [2, 35-36]; it would also presumably have an interaction with related drugs, such as other opiates and GHB. In contrast, taking phenibut with some other drugs, such as stimulants, will more than likely just blunt their effect. In humans, the plasma half-life after a 250 mg oral dose of phenibut is 5.3 hours, and most of the administered drug is excreted unchanged [2]. Reported dosages used in clinical studies range from 250 to 1500 mg daily, usually divided among three doses [2, 37]. Feedback indicates that the ideal dose may be in the higher end of this range. Tolerance develops to many of the effects of phenibut, although it is reported that it does not develop to the nootropic effect. The first signs of tolerance may be seen within as little as five days. For this reason, it is commonly used for one to two week periods, or dosage is increased by 25-30% after two weeks [2]. This makes phenibut ideal for short periods of stress or anxiety, but not ideal for chronic use. It is possible that taking only one dose daily may partially reduce the development of tolerance. If you have any questions or comments regarding this article, please email dvdtlsn@bulknutrition.com References 1. CNS Drug Rev. 2001 Winter;7(4):471-81. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. Lapin I. 2. Pavlov J Biol Sci. 1986 Oct-Dec;21(4):129-40. On neurotransmitter mechanisms of reinforcement and internal inhibition. Shulgina GI. 3. Curr Drug Target CNS Neurol Disord. 2003 Aug;2(4):248-59. GABA(B) receptors as potential therapeutic targets. Vacher CM, Bettler B. 4. Eur J Pharmacol. 1993 Mar 16;233(1):169-72. R-(-)-beta-phenyl-GABA is a full agonist at GABAB receptors in brain slices but a partial agonist in the ileum. Ong J, Kerr DI, Doolette DJ, Duke RK, Mewett KN, Allen RD, Johnston GA. 5. Am J Physiol Gastrointest Liver Physiol. 2001 Aug;281(2):G311-5. Receptors and transmission in the brain-gut axis: potential for novel therapies. IV. GABA(B) receptors in the brain-gastroesophageal axis. Blackshaw LA. 6. Prog Neurobiol. 1995 Jul;46(4):423-62. A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system. Misgeld U, Bijak M, Jarolimek W. 7. Farmakol Toksikol. 1985 Jul-Aug;48(4):50-4. [Differences and similarity in the interaction of fenibut, baclofen and diazepam with phenylethylamine] [Article in Russian]. Lapin IP. 8. Farmakol Toksikol. 1980 May-Jun;43(3):288-91. [Effect of structural analogs of gamma-aminobutyric acid on serotonin- and dopaminergic mechanisms] [Article in Russian]. Nurmand LB, Otter MIa, Vasar EE. 9. Pharmacol Biochem Behav. 1981;14 Suppl 1:53-9. Pharmaco-ethological analysis of social behaviour of isolated mice. Poshivalov VP. 10. Biull Eksp Biol Med. 1987 Nov;104(11):588-90. [Role of the GABAergic system in the mechanism of the stress-regulating action of phenibut] [Article in Russian]. Kovalev GV, Spasov AA, Bogachev NA, Petrianik VD, Ostrovskii OV. 11. Pharmacol Toxicol. 1990 Jan;66(1):41-4. Stress-protection action of beta-phenyl(GABA): involvement of central and peripheral type benzodiazepine binding sites. Rago L, Kiivet RA, Adojaan A, Harro J, Allikmets L. 12. Neurosci Behav Physiol. 2003 Mar;33(3):255-61. Neurochemical characteristics of the ventromedial hypothalamus in mediating the antiaversive effects of anxiolytics in different models of anxiety. Talalaenko AN, Pankrat'ev DV, Goncharenko NV. 13. Eksp Klin Farmakol. 2002 Sep-Oct;65(5):22-6. [Monoaminergic and aminoacidergic mechanisms of the posterior hypothalamus in realization of the antiaversive effects of anxiosedative and anxioselective agents in various anxiety models] [Article in Russian]. Talalaenko AN, Pankrat'ev DV, Goncharenko NV. 14. Ross Fiziol Zh Im I M Sechenova. 2001 Sep;87(9):1217-26. [Neurochemical characteristics of the ventromedial hypothalamus and anti-aversive effects of anxiolytic agents in various anxiety models] [Article in Russian]. Talalaenko AN, Pankrat'ev DV, Goncharenko NV. 15. Eksp Klin Farmakol. 2000 Jan-Feb;63(1):14-8. [The neurochemical profile of the caudate nucleus in the anxiolytic action of benzodiazepine and nonbenzodiazepine tranquilizers on different models of anxiety] [Article in Russian]. Talalaenko AN, Gordienko DV, Markova OP. 16. Ross Fiziol Zh Im I M Sechenova. 1997 Mar;83(3):88-94. [Neurochemical analysis of the amygdala basolateral nucleus of rats during anxiety tests] [Article in Russian] Talalaenko AN, Babii IuV, Perch NN, Vozdvigin SA, Panfilov VIu. 17. Biull Eksp Biol Med. 1984 Feb;97(2):170-2. [Nootropic properties of gamma-aminobutyric acid derivatives] [Article in Russian]. Ostrovskaia RU, Trofimov SS. 18. Farmakol Toksikol. 1984 Jan-Feb;47(1):20-3. [Comparative characteristics of the nootropic action of fenibut and fepiron] [Article in Russian]. Kovaleva EL. 19. Farmakol Toksikol. 1987 Jul-Aug;50(4):18-22. [Normalizing effect of GABA derivatives on late behavioral disorders occurring in rats with early postnatal suppression of protein synthesis] [Article in Russian]. Burov IuV, Ostrovskaia RU, Smol'nikova NM, Trofimov SS, Savchenko NM. 20. Eksp Klin Farmakol. 1994 Mar-Apr;57(2):13-6. [The effect of fenibut on the ultrastructure of the brain mitochondria in traumatic edema and swelling] [Article in Russian]. Novikov VE, Naperstnikov VV. 21. Farmakol Toksikol. 1991 Nov-Dec;54(6):44-6. [The effect of GABA-ergic agents on oxidative phosphorylation in the brain mitochondria in traumatic edema] [Article in Russian]. Novikov VE, Sharov A. 22. Farmakol Toksikol. 1984 May-Jun;47(3):35-8. [Effect of benzodiazepine and GABA derivatives on the energy metabolism indices in brain edema] [Article in Russian]. Novikov VE, Kozlov SN, Iasnetsov VS. 23. Ukr Biokhim Zh. 1984 Nov-Dec;56(6):637-41. [Mg2+-ATPase activity of brain mitochondria fractions in chronic stress and its correction by psychotropic agents] [Article in Russian]. Kresiun VI. 24. Eksp Klin Farmakol. 1992 May-Jun;55(3):70-2. [The effect of GABA-ergic agents on the blood electrolyte balance in acute craniocerebral trauma] [Article in Russian]. Novikov VE, Chemodurova LN. 25. Zh Nevropatol Psikhiatr Im S S Korsakova. 1986;86(8):1146-8. [Phenibut potentiation of the therapeutic action of antiparkinson agents] [Article in Russian]. Gol'dblat IuV, Lapin IP. 26. Farmakol Toksikol. 1991 Sep-Oct;54(5):14-6. [The adequacy of a new method for assessing the vestibular protective effect of biologically active substances] [Article in Russian]. Karkishchenko NN, Dimitriadi NA. 27. Eksp Klin Farmakol. 1997 Jan-Feb;60(1):68-71. [The enhancement of human thermal resistance by the single use of bemitil and fenibut] [Article in Russian]. Makarov VI, Tiurenkov IN, Klauchek SV, Nalivaiko IIu, Antipova AIu. 28. Kardiologiia. 1987 May;27(5):48-52. [Differential psychopharmacotherapy of heart rhythm disorders] [Article in Russian]. Skibitskii VV. 29. Ter Arkh. 1986;58(11):97-101. [Clinico-hemodynamic effects of psychotropic preparations and psychosomatic correlations in cardiac rhythm disorders] [Article in Russian]. Petrova TR, Skibitskii VV. 30. Farmakol Toksikol. 1983 May-Jun;46(3):41-4. [Effect of tranquilizers on myocardial function in stress injury] [Article in Russian]. Kovalev GV, Gurbanov KG, Tiurenkov IN. 31. Farmakol Toksikol. 1983 Jan-Feb;46(1):38-41. [Effect of tranquilizers on the course of myocardial ischemia and on myocardial resistance to hypoxia in coronary artery occlusion] [Article in Russian]. Kovalev GV, Gurbanov KG, Tiurenkov IN, Naidenov SI. 32. Patol Fiziol Eksp Ter. 1995 Jan-Mar;(1):21-3. [Central mechanisms of neurogenic gastric lesion and its pharmacologic correction] [Article in Russian]. Bul'on VV. 33. Biull Eksp Biol Med. 1990 Nov;110(11):504-6. [The effect of GABA-ergic agents on the development of a neurogenic stomach lesion in rats] [Article in Russian]. Bul'on VV, Zavodskaia IS, Khnychenko LK. 34. Farmakol Toksikol. 1989 Jul-Aug;52(4):37-9. [Effect of fenibut and seduxen on fetal development in the second half of pregnancy] [Article in Russian]. Filimonov VG, Sheveleva GA, Strel'chenko NV, Sizov PI, Iasnetsov VS. 35. Biull Eksp Biol Med. 1985 Jun;99(6):698-700. [Effect of fenibut on the GABA B receptors of the spinal motor neurons] [Article in Russian]. Abramets II, Komissarov IV. 36. Arch Immunol Ther Exp (Warsz). 1975;23(6):733-46. Pharmacological properties of gamma-animobutyric acid and it derivatives. IV. Aryl gaba derivatives and their respective lactams. Chojnacka-Wojcik E, Hano J, Sieroslawska J, Sypniewska M. 37. Med Tr Prom Ekol. 1997;(5):35-8. [Experimental bases of the use of pharmacologic agents aimed at higher heat resistance of humans as means of individual protection] [Article in Russian]. Makarov VI, Tiurenkov IN, Klauchek SV, Nalivaiko IO, Antipova AIu. The Hive - Clandestine Chemists Without Borders
		scarmani (Hive Bee) 09-19-04 18:47 No 532191				GABA Reuptake Inhibitors (Rated as: excellent)
						According to anecdotal reports on the internet, the prescription GABA reuptake inhibitor Tiagabine (Gabitril, used as an anticonvulsant and antianxiety medication) causes one to feel drunk: Dissociation constant of 3H labeled Tiagabine in mice: Kd = 72.5 nM    Medline (PMID=1333027) "It might make you feel like you've had a margarita for breakfast...  Side effects: Feeling drunk.  There's no other way to describe it, the first week on Gabitril (tiagabine) is like drinking good Scotch for breakfast.  Eventually it wore down to a pleasant beer buzz, but when that wore off, so did all of its beneficial effects."    http://www.crazymeds.org/gabitril.html "I recently started taking the drug 'Tiagabine', and found that even on one of the lowest doses possible, I was feeling drunk everyday between 12-3pm - falling around and laughing 'til it hurt. Has anybody else had this problem?"    http://neuro-www.mgh.harvard.edu/forum_2/EpilepsyF/7.23.992.10PMTheTroublewi.html This is the official corporate website for Gabitril, which has the animation of the fake synapse (and some free cars and vacations if you prescribe it to all your patients... just kidding.)    http://www.gabitril.com/physicians/home/default.asp ______  _____  ____  ___  __  _ A different GABA uptake inhibitor tested in humans caused "unanticipated severe neurological and psychological side effects."  Code name CI-966, oral bioavailability 100%    Medline (PMID=8272405) Structure-Activity Studies on Benzhydrol-Containing Nipecotic Acid and Guvacine Derivatives as Potent, Orally-Active Inhibitors of GABA Uptake Michael R. Pavia, Sandra J. Lobbestael, David Nugiel, Daniel R. Mayhugh, Vlad E. Gregor, Charles P. Taylor, Roy D. Schwarz, Laura Brahce, and Mark G. Vartanian, J. Med. Chem. 35(22), 4238-4248 (1992) Abstract: The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs.  A series of compounds is reported which explores the structure-activity relationships (SAR) in this series.  Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring.  The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro ICs0 values for GABA uptake of <1 µM (including 5, Table I; 37, 43, Table IV; and 44, Table V).  Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans. The reference given in the paper for detailed report of these "adverse" effects is:                     Initial Human Safety and Tolerance Study of a GABA Uptake Inhibitor, CI-966: Potential Role of GABA as a Mediator in the Pathogenesis of Schizophrenia and Mania.                     Sedman, A. J.; Gilmet, G. P.; Sayed, A. J.; Posvar, E. L.                     Drug. Dev. Res. 1990,21, 235-42. These effects could truly be adverse and undesireable...  On the other hand, it is also possible to infer "euphoric intoxication" from the term mania, or "psychedelic / hallucinogenic / dissociative psychoactivity" from schizophrenia.  This seems reasonable based on the "drunk" effect of Tiagabine.  Another paper looked into the metabolites of CI-966 but these didn't seem to contribute to the unexpected effects: Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride, a gamma-aminobutyric acid uptake inhibitor. Radulovic L, Woolf T, Bjorge S, Taylor C, Reily M, Bockbrader H, Chang T., Chem Res Toxicol. 6(3), 341-344 (1993) Medline (PMID=8318656)  (sidenote; for another interesting paper on neurotoxic /or dopamine uptake inhibiting pyridinium compounds, check out Medline (PMID=1312170) ) [edit] "A randomized, double-blind, escalating single-dose-tolerance, and pharmacokinetic study comparing the effects of CI-966 capsules with those of placebo was conducted in healthy volunteers (6, 7).  The study was terminated at the 50-mg dose due to adverse effects experienced by two female subjects.  Physical signs included unresponsiveness to nonpainful sensory stimuli, tremor, myoclonus, increased muscle rigidity, and cogwheeling.  Short- and long-term memory impairment was also observed. Severity of symptoms appeared to correlate with plasma CI-966 concentration and all physical signs had resolved within 24 h following dosing.  However, psychiatric symptoms resembling those observed in manic and schizophrenic patients lasted for 5 to 6 days in both subjects..." OK so maybe unresponsiveness, myoclonus and cogwheeling do not sound very "fun", not at all.  Nor do I want to make light of mania or schizophrenia which are serious mental conditions.  However after reading this, I still find the compound interesting...  It sounds like the study subjects got a pretty bad overdose and the description of "psychiatric symptoms resembling those observed in manic and schizophrenic patients" is disturbing yet intriguing.  I wonder what a much lower dose would do. [/edit] ______  _____  ____  ___  __  _ Orally Active and Potent Inhibitors of gamma-Aminobutyric Acid Uptake Fadia E. Ali, William E. Bondinell, Penelope A. Dandridge, James S. Frazee, Eleanor Garvey, Gerald R. Girard, Carl Kaiser, Thomas W. Ku, John J. Lafferty, George I. Moonsammy, Hye-Ja Oh, Julia A. Rush, Paulette E. Setler, Orum D. Stringer, Joseph W. Venslavsky, Beth W. Volpe, Libby M. Yunger, and Charles L. Zirklet, Journal of Medicinal Chemistry, 28(5), 653-660 (1985) ______  _____  ____  ___  __  _ NNC-711, a novel potent and selective GABA uptake inhibitor: pharmacological characterization Peter D. Suzdak, Kristen Frederiksen, Knud Erik Andersen, Per 0. Sorensen, Lars J.S. Knutsen and Erik B. Nielsen, Eur J Pharmacol. 224(2-3), 189-198 (1992) "I awoke one morning and electrical maggots were spurting from the mind-control machine.."
		scarmani (Hive Bee) 09-19-04 21:18 No 532206				Potent and Selective GABA-B Agonists (Rated as: good read)
						Phosphinic Acid Analogues of GABA. 1. New Potent and Selective GABA-B Agonists Wolfgang Froestl, Stuart J. Mickel, Roger G. Hall, Georg von Sprecher, Dietrich Strub, Peter A. Baumann, Felix Brugger, Conrad Gentsch, Joachim Jaekel, Hans-Rudolf Olpe, Grety Rihs, Annick Vassout, Peter C. Waldmeier, and Helmut Bittiger, J. Med. Chem. 38(17), 3297-3312 (1995) Abstract: The antispastic agent and muscle relaxant baclofen is a potent and selective agonist for bicuculline-insensitive GABA-B receptors.  For many years efforts to obtain superior GABA-B agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABA-B agonists, the best compounds of which are more potent than baclofen in vitro and in vivo.  They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue.  Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABA-B antagonists, which are described in part 2 of this series.  Structure-activity relationships of the novel GABA agonists are discussed with respect to their affinities to GABA-B receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles. Supporting Info: This paper shows that (3-aminopropyl)methylphosphinic acid (compound 42 in paper, aka CGP 35024, aka SKF 97541, aka APMP, aka Tocris catalog number 0379) is a potent GABA-B agonist, orally active in rats, about 5 times more potent than baclofen by this route. However the paper states that with this compound, "toxic effects were observed at relatively low doses after sc and po administrations."  In contrast the 2-hydroxy-substituted analog (compound 63 in paper) did not produce toxic effects even compared to baclofen, and was close to twice as potent vs. baclofen in rats by oral route. With respect to the reported toxic effects of 3-aminopropyl(methyl)phosphinic acid, it's also worth mentioning that this compound has been looked at as an insecticide which kills flies and cockroaches... Medline (PMID=10190056) boot from the shadow of a broken mirror
		Fastandbulbous (Hive Bee) 09-21-04 01:00 No 532405				A simple GABA agonist and reuptake inhibitor
						Oops, I've noticede that I've already posted something abot TACA a while ago in this thread. Sorry. So I'll just leave the Tocris entry for refs That is right, the Mascara Snake: Fast and bulbous
		scarmani (Hive Bee) 09-21-04 10:36 No 532476				TACA (Rated as: good read)
						I do not think TACA would be centrally active, because it wouldn't cross the blood brain barrier very well (similar to GABA).  The other compound you mentioned, trans-4-hydroxycrotonic acid, would probably cross the blood-brain barrier based on its similarity to GHB.  However, it is not a ligand at GABA-B and doesn't seem to have the same effects as GHB: Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid M. Paola Castelli, Luca Ferraro, Ignazia Mocci, Francesca Carta, Mauro A. M. Carai, Tiziana Antonelli, Sergio Tanganelli, Giorgio Cignarella and Gian Luigi Gessa, Journal of Neurochemistry. 87(3), 722–732 (2003) DOI:10.1046/j.1471-4159.2003.02037.x Abstract: Two gamma-hydroxybutyric acid (GHB) analogues, trans-gamma-hydroxycrotonic acid (t-HCA) and gamma-(p-methoxybenzyl)-gamma-hydroxybutyric acid (NCS-435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABA-B receptors.  The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared.  While GHB and baclofen stimulated 5'-O-(3-[35S]thiotriphospate) [35S]GTP-gamma-S binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mM concentration.  GHB and baclofen effect was suppressed by the GABA-B antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382.  Perfused into rat hippocampus, 500 nm and 1 mm GHB increased and decreased extracellular glutamate levels, respectively.  GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348.  t-HCA and NCS-435 (0.1-1000 µM) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 µM) but not by CGP 35348 (500 µM).  The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABA-B-mediated effects, while the increase of glutamate levels is a GHB-mediated effect.  Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABA-B-mediated.  The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor. Nevertheless, it seems that GHB is partially metabolized to GABA: Post 485323 (Rhodium: "GHB Neurobiology & Tertiary alcohol analog", General Discourse)  "GHB is formed in the brain from GABA-derived succinic semialdehyde (SSA) via a specific succinic semialdehyde reductase (SSR).  GHB can be reconverted back to SSA via GHB dehydrogenase, and the GHB-derived SSA can be converted back to GABA..."  So maybe there is still the possibility that after crossing BBB, trans-4-hydroxycrotonic acid would be partially converted to TACA in vivo and exert additional effects... tobacco smoking doesn't cause cancer: people cause cancer
		Rhodium (Chief Bee) 10-14-04 23:46 No 535880				GS39783: A "Benzo" for GABA-B Receptors
						More Reading about GS39783 can be found in Post 510235 (scarmani: "Baclofen and Novel "GABAergics"", General Discourse) N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid-B Receptor Function Stephan Urwyler, Mario F. Pozza, Kurt Lingenhoehl, Johannes Mosbacher, Christina Lampert, Wolfgang Froestl, Manuel Koller, and Klemens Kaupmann, J. Pharm. Exp. Therap. 307, 322-330 (2003), DOI:10.1124/jpet.104.066753 Abstract N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds are described as novel allosteric enhancers of GABAB receptor function. They potentiate GABA-stimulated guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding to membranes from a GABAB(1b/2)-expressing Chinese hamster ovary cell line at low micromolar concentrations, but do not stimulate [35S]GTPγS binding by themselves. Similar effects of GS39783 are seen on native GABAB receptors in rat brain membranes. Concentration-response curves with GABA in the presence of different fixed concentrations of GS39783 reveal an increase of both the potency and maximal efficacy of GABA at the GABAB(1b/2) heterodimer. In radioligand binding experiments, GS39783 reduces the kinetic rate constants of the association and dissociation of [3H]3-aminopropylphosphinic acid, resulting in a net increase in affinity for the agonist radioligand. In equilibrium binding experiments (displacement of the antagonist ligand [3H]CGP62349), GS39783 increases agonist affinities. Agonist displacement curves are biphasic, probably reflecting the G protein-coupled and uncoupled states of the receptor. The proportion of the high-affinity component is increased by GS39783, suggesting that the G protein coupling of the receptor is also promoted by the positive modulator. We also show that GS39783 has modulatory effects in cellular assays such as GABAB receptor-mediated activation of inwardly rectifying potassium channels in Xenopus oocytes and Ca2+ signaling in human embryonic kidney 293 cells. In a more physiological context, GS39783 is shown to suppress paired pulse inhibition in rat hippocampal slices. This effect is reversed by the competitive GABAB receptor antagonist CGP55845A and is produced most likely by enhancing the effect of synaptically released GABA at presynaptic GABAB receptors. Synthesis: Herbicidal and plant growth regulating 2-(alkylthio)-4,6-diamino-5-nitropyrimidine derivatives Fischer H, Patent DE2223644 (1972) (Patent GB1393993) Nitropyrimidine plant growth regulators [herbicides] Fischer H, Patent DE2356644 (1974) (Patent US3948914) 5-Nitropyrimidine derivatives and their use as plant growth regulators Fischer H, Patent DE2520381 (1975) (Patent US4014677) The Hive - Clandestine Chemists Without Borders

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