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Gamma-Hydroxybutyrate (GHB) and Its Derivatives: a New and Novel Neuroactive Drug of Abuse

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Chula Mad J Vol. 48 No.7 July 2004 Gamma-Hydroxybutyrate (GHB) and its derivatives: A new and novel neuroactive drug of abuse Krisda Sirampuj* Sirampuj K. Gamma-Hydroxybutyrate (GHB) and its derivatives: A new and novel neuroactive drug of abuse. Chula Med J 2004 Jul; 48(7): 491 - 502 There has been increasing attention in the abuse of gamma-hydroxybutyrate (GHB) , with some evidence in other parts of the world especially the United States. In vitro and animal research models show that, while GHB shares certain properties with some depressant drugs abusive to central nervous system, it also has unique aspects of its pharmacology including actions at a specific neural receptor which probably mediates many of its effects. So far, the assessment of the abusive potential of GHB with standard animal models has not yielded a picture of a highly abusive substance, and little testing of the drug in human has been done. Vel}' little systematic data exist on the tolerance and dependence of GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of GHB abuse began in the late 1980s and continues to the present. GHB is often included with the group of the so-called 'club drugs', which can be used as an intoxicant. It also has been used as a growth promoter and sleep-aid agent, also implicated in cases of 'date rape', usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. With as yet unknown consequences for the scope of the public health problem, recent changes in the control status of GHB in the US may reduce its availability. Experts on drug abuse need to familiarize themselves with GHB since it has a potentiality to be a new type of problem of drug abuse with some unique properties. Keywords: Gamma-hydroxybutyrate, GHB, Gamma-butyrolactone, GBL, Novel neuroactive drug, New type of drug abuse. Reprint request: Sirampuj K. Faculty of Liberal Arts, Thammasat University, Khong Luang, Prathum Thani 12121, Thailand. E-mail: [email protected] Received for publication: May 15, 2004. Objective: This review highlights the biochemistry, neuropharmacology, and toxicology of the naturally­ occurring fatty acid derivative, gamma-hydroxybutyrate (GHB). GHB is derived from gamma­ aminobutyric acid (GABA) and is proposed to function as an inhibitory chemical transmitter in the central nervous system. The purposes ofthis review also focus on the social effect of this substance and urge the public to aware of its increasing abuse potential. • Faculty of Liberal Arts, Thammasat University 492 Chula Med J n"IV"1 fi"i1 a.I"1tf. un a.I a.l11U""ifl nfJih 1 'VI L"i'VI LUU~fl~\iU 6' if1"ifl fl n"I 'VI BPi flij"t1"i~if1'V1 s11 'l'HaJ;iemha.l1'lllu'VI1,,;iel6l. ~\11ft"n"ialL 1tfif1"i 2547 n.Ft; 4S( 7): 491 - 502 Luiflil~ uuiJ n lr LUf"l,]IU~U Liii LU dfN'!JfJ-Jmr HEJl'll~fJ~ lrdfJfJn q'VIfPifJ'iPllh::~ 1 'VI LU'VJ1-J dCJ(i1Uln~U ~ lrLLnUUl LeJ(i1rfJn~fj'] L'VJLmviffi GHB dju~lrfJfJn q'VIfPl'fJ'iPll1r::~ 1 'VI df"l'fJ U;[I-J L'VI:J P7,]'VId-Jdril;-Jdjuifty'VI1~IFity'VJ1-J~lfjln1J~'!J GHB fJfJnq'VIfPifJP7']flJdr./I'rn::'!JfJ-Jr::lJlJl1r::~I'V1 fI']un~l-J ~-JrifJ LU"7(i1t:J~PifJ~UfJ-JLU'VI~IEJ~IU iJmr~n'1Yln-Jt:J~'~EJ'!JfJ-J GHB fJcJl-JUln LuiPl{ 'VI(i1 ~fJ.J LLPI'n 6-J L:JL~IlIWdi(i1' IiIUfJfJ nUl fI ']u LUU'lf'1Y66-JiJ n lr~n '1Y1UfJ EJUI n iJLLPi;[fJ3J~ "rEJ']t7lJ nlrfJfJnq'VIfLu~lunlmuPifJq'VIfEJ1LL~::nlr'~W~(i1 ;[fJ3J~ LU~lulEUlru'!JfJ-Jf"l,]IU1nmrH~lr GHB LL~::fJ'lfWUfj1U'VJ1-JdL:JL'V/Ul::~u6-JL:JiJ ,.... '1,1 P1,]'~'!J)?i(i1'IiIU LLPI'liIlnmr:;i(i1'V11-J~IUFJrulllWWlJlhiJmrUilu'VI1-J)?CJ(i1fJcJl-JLLWi'VI~IEJP7-JLLPi"ll,]-J l1~IEJ'VIMrr'1Y 1980 liIun-Jiflil~uu ~lr GHB 3J'nQnL-rlu'VI3J";mdmn~I-J~UliluiJ~fJLrEJn11 'EJld L-rlUf"l;lJ' UfJnlillna GHB 6-JQn'-%dju~lrL'~ungfl,i!fJLL~::mr'liI~ty'~lJLPlLurJLW1::mEJLL~::H ,iJUEJ1UfJU 'VI;lJ LurJd iJ ifty'VIl n1 rUfJ U LUlJl-Jf"l n'] Hi']u t711fr~ nfJ eJf1ffi ~fJ m r~'fJ ~,]-J'VI l-J' WPI " J,I .., , ,ilfJ-J1iI In)? ehUUl n lr'VI1~fJ~ lr GHB LL~::~ 1 rP7-Jtlru)?L-rlumrt:JflPlf"l'fJU;[I-J,h EJ~-Jnl LUiJlEUI ru , , ., mrL-%)?~-J "PI'Luiflil~UU LU~'VIf.!fJ,u~m L~iJmr,l1ftEJumJ~-J L(i1EJril'V1U(i1 LU GHB "~::~lrP7-Jtlru ,iJu~lrdfJ~LUnfJ'Uf"l,]lJFJUUln~U '~fJiJfJ-Jt7Uifty'VI1'V11-J~lfjlrru~'!Jdd7(i11i11nmrL-%EJ1CJ(i1iPlfJ l1r::~-Jrr ..., , , U'VI f"l,]IUi1iJ~ (i1l1r::~ -J mWfJ LulJ f"l ~ 1 m'VJ1-J~ lfjlrru~'!J, rJiJfllUlli1)? Lf7 m;[fJ-J Lum rf"l,]u FJU , , 'I" '1 .col... • I It .,..,., .., - .col nlr &'lfEJI &U'VJ1-J'VIt:J(i1, "~::ur::'lfl'lfU &(i1P1r::'VIun"~::'VInu'!JfJ3J~'!JfJ-J~lr GHB "~::fJ'lfWUfj'11-JU "U'] Luudlil::iJ m r L-rl U'VI l-Jd, 'VIU1::~ u "~::fJlli1 LiJU~ 1 rL~ W~ WJ1iJ(i1 L'VI:Jd':h 1l1~ifty'VI1'V1 l-Ji-Jf"lU LL~::~lfjlrru~'!J Pi1Ihfi'Y: LLnUUl LeJ(i1rfJn~fj'] L'VIL~PI, "nUU1U'] 1'VI L~"~n LPlU, EJlfJfJnq'VIfPifJ~Pll1~::~I'V1P7,] L'VI:J, EJldL-rlunl~~'fJ~,]-J'VI1-JLWPI Vol. 48 No.7 493 July 2004 Gamma-Hydroxybutyrate (GHB; 4-hydro­ its hypnotic effects and its ability to incapacitate xybutyrate, 4-hydroxybutyric acid) is a central victims (mostly women) for purposes of sexual neuromodulator synthesized locally from Gamma­ assault. GHB produces a state of relaxation and aminobutyric acid(GABA) which is an endogenous tranquility accompanied by feelings of calmness, mild constituent of mammalian brains. Synthetic GHB was euphoria. As the dose of these drugs is increased, a initially developed as anesthetic agents and was sold sharp increase in adverse effects may occur. in the US in health food store as a performance Overdoses with these drugs can result in life­ enhancing additive in bodybuilding formulas. However threatening symptoms of CNS depression, coma, in 1990, the US Food and Drug administration (FDA) respiratory depression, apnea, bradycardia, banned its distribution due to its widespread reports hypotension, and seizures.(3) According to the Drug of poisoning and adverse reactions. In 2000, GHB Abuse Warning Network (DAWN), GHB emergency was placed into schedule I of the Federal Controlled department mentions have increased from 56 in 1994 Substance Act.(1) to 3,340 in 2001. Since 1990, the US Drug Enforcement Administration (DEA) has documented more than Abusive use of GHB 15,600 overdoses and law enforcement encounters Despite being banned by the FDA, GHB is and 72 deaths related to GHB. The FDA has released still widely available in the underground drug market. reports and warning conveying the adverse health There are analogs of GHB; Gammabutyrolactone consequences of GHB, GBL, and 1,4-butanediol. (GBL) and 1,4-butanediol which are marketed as Ingestion of the products containing these substances dietary supplements in health food stores, sport have been linked to at least 122 serious illnesses and nutrition stores and on the internet. GBL is converted three deaths. (2) The FDA has issued warnings for both into GHB in an alkaline environment such as in the GBL and 1,4-butanediol, stating that the drugs presence of sodium or potassium hydroxide and the have a potential for abuse and are a public health reaction is complete in under an hour. Additionally, danger.(1) once digested these analogs of GHB are rapidly metabolized to GHB in vivo by a rapidly acting Situation in Thailand lactonase found in the blood and liver. 1,4-butanediol In 2003, the Food and Drug Administration of is converted to GHB by alcohol dehydrogenase and Thailand reported death of a woman and seven cases aldehyde dehydrogenase. Due to the efficient of serious illness resulted from drinking wine that conversion of both GBL and 1,4-butanediol, their contains GBL, tetrahydrofuran (THF), and acetonitrile toxicological profiles are essentially analogous to that or methyl cyanide.(4.5) The wine was in a lot of 144 of GHB.(2) bottles which two foreigners had been hired to mail Factors that seem to contribute to the the bottles to the US but the company was unable to addictive potential of GHB and its metabolic send it. (4) precursors include its purported anabolic effects, 494 Chula Med J Biotransformation of GHB and THF effects such as behavioral sedation and narcosis in Comparing the structures of GBL with 1, mammals, gastrointestinal tract like nausea, vomiting 4-butanediol and THF, itwas found that each of these and diarrhea and may cause respiratory depression, compounds share the same 4-carbon backbone and coma, and death. Overdose of GHB can cause life­ the differences between them are due to the different threatening effects similar to acute THF toxicity, such functional groups at the C-1 and C-4. Hydrolysis of as respiratory depression, apnea, hypotension, coma GBL opens the 5-membered ring of the 4-carbon and death. Currently there are no antidotes to treat backbone, forming GHB. Conversions of these GHB overdose or THF toxicity. Knowledge about the structure are as follows: the conversion of 1, biotransformation of THF to GHB could be useful in 4-butanediol to THF can be accomplished by designing pharmacological interventions.
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    THE EFFECTS OF CHRONIC ETHANOL INTAKE ON THE ALLOSTERIC INTERACTION BE T WEEN GABA AND BENZODIAZEPINE AT THE GABAA RECEPTOR THESIS Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements For the Degree of MASTER OF SCIENCE By Jianping Chen, B.S., M.S. Denton, Texas May, 1992 Chen, Jianping, The Effects of Chronic Ethanol Intake on the Allsteric Interaction Between GABA and BenzodiazeDine at the GABAA Receptor. Master of Science (Biomedical Sciences/Pharmacology), May, 1992, 133 pp., 4 tables, 3.0 figures, references, 103 titles. This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes. ACKNOWLEDGEMENT I would like to express my sincere thanks to my major professor, Dr. Michael W. Martin. .I deeply appreciate his guidance and direction which initiated this study, and his kindness in sharing his laboratory facilities with me. His suggestions, patience, encouragement and support in the laboratory have contributed significantly to my understanding of the receptor mechanism of drug action.
  • Properties, Synthesis and Transformations Pedro M

    Properties, Synthesis and Transformations Pedro M

    molecules Review ReviewStyrylpyrazoles: Properties, Synthesis and Styrylpyrazoles:Transformations Properties, Synthesis and Transformations Pedro M. O. Gomes, Pedro M. S. Ouro, Artur M. S. Silva * and Vera L. M. Silva * PedroLAQV-REQUIMTE, M. O. Gomes Department, Pedro M.of Chemistry, S. Ouro, Artur University M. S. of Silva Aveiro, * 3810-193and Vera Aveiro, L. M. Portugal; Silva * LAQV-REQUIMTE,[email protected] (P.M.O.G.); Department [email protected] of Chemistry, University(P.M.S.O.) of Aveiro, 3810-193 Aveiro, Portugal; [email protected]* Correspondence: (P.M.O.G.); [email protected] [email protected] (A.M.S.S.); (P.M.S.O.) [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); * Correspondence:+351-234-370704 (V.L.M.S.) [email protected] (A.M.S.S.); [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); +351-234-370704 (V.L.M.S.) Academic Editor: Derek J. McPhee Academic Editor: Derek J. McPhee Received: 21 November 2020; Accepted: 9 December 2020; Published: date Received: 21 November 2020; Accepted: 9 December 2020; Published: 12 December 2020 Abstract: The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged Abstract:scaffolds inThe medicinal pyrazole chemistry nucleus and due its to reduced their rema forms,rkable pyrazolines biological and activities. pyrazolidine, A huge are number privileged of scapyrazoleffolds inderivatives medicinal have chemistry been duestudied to their and remarkablereported over biological time. activities.This review A hugearticle number gives an of pyrazoleoverview derivatives of pyrazole have derivatives been studied that and contain reported a styryl over time.