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.

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.

Department of Pharmacology, Tartu University, Estonia, USSR.

Forced swimming stress caused a significant increase in the density of central type benzodiazepine binding sites in rat cerebral cortex and hippocampus. The number of peripheral type benzodiazepine binding sites was also enhanced on blood platelets. The affinity of neither central nor peripheral type benzodiazepine binding sites was changed considerably after swimming stress. Pretreatment of rats with beta-(phenyl)GABA (100 mg/kg), a GABAB agonist, almost completely eliminated the described changes of the both types of benzodiazepine binding sites caused by swimming stress. In an elevated plus-maze model of anxiety beta-(phenyl)GABA itself was inactive but like diazepam effectively counteracted the behavioural effects of DMCM, a beta-carboline derivative with anxiogenic properties. The possible involvement of benzodiazepine receptors in the mechanism of action of beta-(phenyl)GABA is discussed.

Differing actions of beta-phenyl-GABA and baclofen in the guinea pig isolated ileum.

Ong J, Kerr DI, Johnston AR.

In the guinea-pig isolated ileum, both gamma-aminobutyric acid (GABA) and baclofen induced a dose-dependent depression of cholinergic twitch contractions to transmural stimulation, sensitive to delta-aminovaleric acid (DAVA) and phosphonobaclofen (phaclofen). beta-Phenyl-GABA (BPG) antagonised this depressant action of baclofen and GABA, whilst itself weakly depressing ileal twitch contractions, an effect insensitive to DAVA or phaclofen, and thus unrelated to any GABAB-receptor-mediated effects. These results suggest that the baclofen receptors in the ileum that are antagonised by BPG differ from either of baclofen receptors in the spinal cord, where the presynaptic receptors are blocked by phaclofen and the postsynaptic receptors are insensitive to phaclofen, with BPG having baclofen-like actions at both sites. Interaction of BPG and baclofen with different receptor populations may explain the differing therapeutic actions of these compounds.

Mg2+-ATPase activity of brain mitochondria fractions in chronic stress and its correction by psychotropic agents

Kresiun VI

Ukr Biokhim Zh (USSR) Nov-Dec 1984, 56 (6) p637-41

The activity of Mg2+-ATPase was determined in the cortex mitochondrial fraction, limbic system and medulla oblongata under conditions of chronic stress as well as against a background of preliminary therapy by psychotropic drugs. At the inanition stage of animals the chronic stress is shown to inhibit sharply the process of respiration and phosphorylation (by dissociation) and to decrease the content of brain macroergs. The activity of Mg2+-ATPase in the mitochondrial fractions is lowered. It practically restores to the control level against a background of stress with preliminary course of administering nicotinic acid and GABA derivatives (lithonite, nicogamol and phenibut) to rats in average therapeutic doses. Mebicar, meprobamate and chlorodiazepoxide produce a less pronounced normalizing effect on the activity under study. It is substantiated to be expedient to apply psychotropic drugs as stress-protectors for normalization of energy metabolism of brain neurons.

Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: A pilot study

Psychoneuroendocrinology (United Kingdom), 1997, 22/1 (25-38)

Premenstrual syndrome (PMS) is characterized by cyclical changes in psychological and physical symptoms related to the formation of the corpus luteum and the fluctuations of gonadal hormones. Ovarian steroids have direct effects on neurotransmission, exemplified by the binding of certain metabolites of progesterone to the gamma-amino-butyric acid (GABA(A)) receptor where they exert a facilitating effect on inhibitory neurotransmission. There is also evidence for steroids with inverse-agonist actions on the GABA(A)-receptor with opposite effects on the GABAergic transmission. The purpose of this pilot study was to examine a possible decrease in GABA(A)/benzodiazepine-receptor sensitivity in PMS patients using saccadic eye velocity and self-ratings of sedation as dependent measures. Seven patients with proven PMS and seven control subjects were recruited for the study. Saccadic eye velocity (SEV) and visual analogue ratings for sedation and mood were measured after increasing doses of placebo and diazepam. The PMS patients responded with a significantly less decrease in saccadic eye velocity after benzodiazepine injections compared with control subjects, the difference being most prominent in the luteal phase. This group difference was due to an increased SEV responsiveness to benzodiazepines among control subjects in the luteal phase compared with the follicular phase. The PMS patients in the luteal phase responded with less increase in sedation change scores following benzodiazepine injections compared with control subjects. This group difference in the luteal phase was due to a decreased sedation response to benzodiazepines across the menstrual cycle in the PMS patients. There was no correlation between sedation change scores and SEV in PMS patients. These results support evidence for a reduced or dysregulated sensitivity at the GABA(A)/benzodiazepine-receptor complex in patients with PMS.

Additional References & Abstracts Can Be Found Below:

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.