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Review

The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics

Pages 601-618 | Published online: 31 May 2005

Bibliography

  • ESTES JW: The road to tranquility: the search for selective anti-anxiety agents. Synapse (1995) 21:10–20.
  • ARGYROPOULOS SV, NUTT DJ: The use of benzodiazepines in anxiety and other disorders. Eur. Neuropsychopharmacol. (1999) 9\(Suppl. 6):S391–S392.
  • SHADER RI, GREENBLATT DJ: Use of benzodiazepines in anxiety disorders. N Engl. J. Med. (1993) 328:1398–1405.
  • GORMAN JM: Treating generalized anxiety disorder. J. Clin. Psychiatry (2003) 64\(Suppl. 2):24–29.
  • WOODS JH, WINGER G: Current benzodiazepine issues. Psychopharmacol (1995) 118:107–115.
  • •Review of issues associated with the abuse and physical dependence liabilities of BZs.
  • BUFFET-JERROTT SE, STEWART SH: Cognitive and sedative effects of benzodiazepine use. Curr. Pharm. Des. (2002) 8:45–58.
  • CUMMING RG, LE COUTER DG: Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs (2003) 17:825–837.
  • SCHWEIZER E, RICKELS K: Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Acta Psychiatr. Scand. Suppl. 1998(1998) 393:95–101.
  • CHOUINARD G: Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. j. Clin. Psychiatry (2004) 65 (Suppl. 5):7–12.
  • FRICCHIONE G: Clinical practice. Generalized anxiety disorder. N Engl. Med. (2004) 351:675–682.
  • ASHTON H: Benzodiazepine abuse. In: Drink, Drugs and Dependence - From Science to Clinical Practice. Caan W, de Belleroche J (Eds) London, UK (2002):197–211.
  • ROBERTSON JR, TREASURE W: Benzodiazepine abuse - nature and extent of the problem. CNS Drugs (1996) 5:137–146.
  • WOODS JH: Problems and opportunities in regulation of benzodiazepines. ./. Clin. Pharmacol (1998) 38:773–782.
  • WOODS JH, WINGER G: Abuse liability of flunitrazepam.j. Cliii. Psychopharmacol (1997) 17\(Suppl. 2):1S–575.
  • GRIFFITHS RR, WOLF B: Relative abuse liability of different benzodiazepines in drug abusers. ./. Cliii. Psychopharmacol (1990) 10:237–243.
  • WEINTRAUB M, SINGH S, BYRNE L, MAHARAJ K, GUTTMACHER L: Consequences of the 1989 New York State triplicate benzodiazepine prescription regulations. I Am. Med. Assoc. (1991) 266:2392–2397.
  • UHLENHUTH EH, BALTER MB, BAN TA, YANG K: International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. J. Clin.Psychopharmacol. (1999) 19\(Suppl. 2):23S–29S.
  • UHLENHUTH EH, BALTER MB, BAN TA, YANG K: Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992–1997. Eur. Neuropsychopharmacol. (1999) 9\(Suppl. 6):S393–S398.
  • COSTA E, GUIDOTTI A, MAO CC: Evidence for involvement of GABA in the action of benzodiazepines: studies on rat cerebellum. Adv. Biochem. Psychopharmacol (1975) 14:113–130.
  • HAEFELY W, KULCSAR A, MOHLER H, PIERI L, POLC P, SCHAFFNER R: Possible involvement of GABA in the central actions of benzodiazepines. Adv. Biochem. Psychopharmacol. (1975) 14:131–151.
  • CHOI DW, FARB DH, FISCHBACH GD: Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature (1977) 269:342–344.
  • BRAESTRUP C, SQUIRES RF: Specific benzodiazepine receptors in rat brain characterized by high-affinity 3H-diazepam binding. Proc. Nati Acad. Sci. USA (1977) 74:3805–3809.
  • MOHLER H, OKADA T: Properties of PHI diazepam binding to benzodiazepine receptors in rat cerebral cortex. Life Sci. (1977) 20:2101–2110.
  • MOHLER H, OKADA T: The benzodiazepine receptor in normal and pathological human brain. BE I Psychiatry (1978) 133:261–278.
  • TALLMAN JF, GALLAGHER DW: The GABA-ergic system: a locus of benzodiazepine action. Ann. Rev Neurosci. (1985) 8:21–44.
  • HILL DR, BOWERY NG: 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature (1981) 290:149–152.
  • KLEPNER CA, LIPPA AS, BENSON DI, SANO MC, BEER B: Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem. Behav. (1979) 11:457–462.
  • SQUIRES RF, BENSON DI, BRAESTRUP C et al.: Some properties of brain specific benzodiazepine receptors: New evidence for multiple receptors. Pharmacol Biochem. Behav. (1979) 10:825–830.
  • BRAESTRUP C, NIELSON M: PHIPropy113-carboline-3-carboxylate as a selective ligand for the BZ1 benzodiazepine receptor subclass. J. Neurochem. (1981) 37:333–341.
  • SIEGHART W, SCHUSTER A: Affinity ofvarious ligands for benzodiazepine receptors in rat cerebellum and hippocampus. Biochem. Pharmacol (1984) 33:4033–4038.
  • SIGEL E, BARNARD EA: A y-aminobutyric acidibenzodiazepine receptor complex from bovine cerebral cortex. Improved purification with preservation of regulatory sites and their interactions. J. Biol Chem. (1984) 259:7219–7223.
  • SCHOFIELD PR, DARLISON MG, FUJITA N et al: Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature (1987) 328:221–227.
  • LEVITAN ES, SCHOFIELD PR, BART DR et al.: Structural and functional basis for GABAA receptor heterogeneity. Nature (1988) 335:76–79.
  • PRITCHETT DB, LUDDENS H, SEEBURG PH: Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science (1989) 245:1389–1392.
  • BARNARD EA, SKOLNICK P, OLSEN RW et al.: International Union of Pharmacology. XV. Subtypes of y-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev (1998) 50:291–313.
  • •Review of the classification and nomenclature of GABAA receptors.
  • CROMER BA, MORTON CJ, PARKER MW: Anxiety over GABAA receptor structure relieved by AChBP. Trends Biochem. Li. (2002) 27:280–287.
  • SIMON J, WAKIMOTO H, FUJITA N, LALANDE M, BARNARD EA: Analysis of the set of GABAA receptor genes in the human genome. I Biol. Chem. (2004) 279:41422–41435.
  • BORMAN J: The 'ABC of GABA receptors. Trends Pharmacol Li. (2000) 21:16–19.
  • McKERNAN RIVI, WHITING PJ: Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. (1996) 19:139–143.
  • SIEGHART W, SPERK G: Subunit composition, distribution and function of GABAA receptor subtypes. Curr. Top. Med. Chem. (2002) 2:795–816.
  • MINIER F, SIGEL E: Techniques: use of concatenated subunits for the study of ligand-gated ion channels. Trends Pharmacol Sci. (2004) 25:499–503.
  • SIEGHART W: Structure and pharmacology of y-aminobutyric acidA receptor subtypes. Pharmacol Rev (1995) 47:181–234.
  • ••Detailed review of the pharmacology of thenumerous binding sites on the GABAA receptors.
  • PRITCHETT DB, SEEBURG PH: y-aminobutyric acidA receptor a5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. (1990) 54:1802–1804.
  • WISDEN W, HERB A, WEILAND H, KEINAN K, LUDDENS H, SEEBURG PH: Cloning, pharmacological characteristics and expression pattern of rat GABAA receptor a4 subunit. FEBS Lett (1991) 289:227–230.
  • WIELAND HA, LUDDENS H, SEEBURG PH: A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. (1992) 267:1426–1429.
  • •Original description of how a single histidine residue determines the binding of diazepam to al-,112 a3- and a5- but not a4- or a6-containing GABAA.
  • BENSON JA, LOW K, KEIST R, MOHLER H, RUDOLPH U: Pharmacology of recombinant y-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated a-subunits. FEBS Lett (1998) 431:400–404.
  • ••Characterisation of recombinant GABAAreceptors containing point mutated a-subunits and recognition of the Importance of key histidine residue in not only determining affmity of diazepam, but also the efficacy of other ligands such as bretazenil and Ro-15–4513. Also, description of potential in vivo uses of point-mutated a-subunits.
  • RUDOLPH U, MOHLER H: Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. AMU. Rev Pharmacol Toxicol. (2004) 44:475–498.
  • MOROZ G: High-potency••benzodiazepines: recent clinical results. Clin. Psychiatry (2004)65 (Suppl. 5):13–18.
  • HUNKELER W, MOHLER H, PIERI L59.et al.: Selective antagonists of benzodiazepines. Nature (1981)290:514–516.
  • WISDEN W, LAURIE DJ, MONYER H, SEEBURG PH: The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. Neurosci. (1992) 12:1040–1062.
  • FRITSCHY J-M, MOHLER H: GABAA receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits. J. Comp. Neurol (1995) 359:154–194.
  • SPERK G, SCHWARZER C, TSUNASHIMA K, FUCHS K, SEIGHART W: GABAA receptor subunits in the rat hippocampus: I. Immuncytochemical distribution of 13 subunits. Neuroscience (1997) 80:987–1000.
  • PIRKER S, SCHWARZER C, WIESELTHALER A, SIEGHART W, SPERK G: GABAA receptors: Immunocytochemical distribution of 13 subunits in the adult brain. Neurosci. (2000) 101:815–850.
  • ROSAHL TW: Validation of GABAA receptor subtypes as potential drug targets by using genetically modified mice. Curr. Drug Targets - CNS Neurol Dis. (2003) 2:53–59.
  • BOEHM II SL, PONOMAREY I, JENNINGS AW et al: y-Aminobutyric acidA receptor subunit mutant mice: new perspectives on alcohol actions. Biochem. Pharmacol (2004) 68:1581–1602.
  • CRESTANI F, ASSANDRI R, TAUBER M, MARTIN JR, RUDOLPH U: Contribution of the al-GABAA receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology (2002) 43:679–684.
  • KOPP C, RUDOLPH U, TOBLER I: Sleep EEG changes after zolpidem in mice. Neuroreport (2004) 15:2299–2302.
  • RUDOLPH U, CRESTANI F, BENKE D et al.: Benzodiazepine actions mediated by specific y-aminobutyric acidA receptor subtypes. Nature (1999) 401:796–800.
  • •• Initial description of the in vivo use of point-mutated al-subunit (H101R) to establish the role of al-containing GABAA receptors in sedative effects of diazepam.
  • McKERNAN RM, ROSAHL TW, REYNOLDS DS et al: Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor ai subtype. Nat. Neurosci. (2000) 3:587-592. Confirmation of the importance of the al-subunit in mediating sedative effects of diazepam using a1-H101R mice. Also, first description of the prototypic, efficacy selective compound L-838417 and its non-sedating anxiolytic properties in rodents.
  • LOW K, CRESTANI F, KEIST R et al: Molecular and neuronal substrate for the selective attenuation of anxiety. Science (2000) 290:131–134.
  • ••Use of a2-H101R and a3-H126R point-mutated mice to demonstrate the role of a2-containing GABAA receptors in determining anxiolytic efficacy of diazepam.
  • CRESTANI F, LOW K, KEIST R, MANDELLI M-J, MOHLER H, RUDOLPH U: Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. (2001) 59:442–445.
  • TOBLER I, KOPP C, DEBOER T, RUDOLPH U: Diazepam-induced changes in sleep: role of the al GABAA receptor subtype. Proc. Natl. Acad. Li. USA (2001) 98:6464–6469.
  • KOPP C, RUDOLPH U, KEIST R, TOBLER I: Diazepam-induced changes on sleep and the EEG spectrum in mice: role of the a3-GABAA receptor subtype. Eur. Neurasci. (2003) 17:2226–2230.
  • CRESTANI F, KEIST R, FRITSCHY J-M et al: Trace fear conditioning involves hippocampal a5 GABAA receptors. Proc. Nati Acad. Sci. USA (2002) 99:8980–8985.
  • •Generation of a5H105R point-mutated mice resulted in decreased hippocampal expression of a5-containing GABAA receptors. As a result, mice had altered trace fear conditioning, suggesting a role for this receptor subtype in cognition.
  • COLLINSON N, KUENZI FM, JAROLIMEK W et al.: Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the a5 subunit of the GABAA receptor. Neurosci. (2002) 22:5572–5580.
  • CHAMBERS MS, ATACK JR, CARLING RW et al: An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA a5 receptors with cognition enhancing properties. J. Med. Chem. (2004) 47:5829–5832.
  • STERNFELD F, CARLING RW, JELLEY RA et al.: Selective, orally active y-aminobutyric acidA 15 receptor inverse agonists as cognition enhancers. J. Med. Chem. (2004) 47:2176–2179.
  • STREET LJ, STERNFELD F, JELLEY RAet al.: Synthesis and biological evaluation of 3-heterocycly1-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo13,4-alphthalazines and analogues as subtype-selective inverse agonists for the GABAA a5 benzodiazepine binding site. J. Med. Chem. (2004) 47:3642–3657.
  • ATACK JR, HUTS ON PH, COLLINSON N et al: Anxiogenic properties of an inverse agonist selective for a3 subunit-containing GABAA receptors. BE J. Pharmacol (2005) 144:357–366.
  • •Description of the anxiogenic properties of an a3-selective inverse agonist.
  • LE DOUX JE: Emotion circuits in the brain. Ann. Rev Neurasci. (2000) 23:155–184.
  • WALKER DL, TOUFEXIS DJ, DAVIS M: Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur..I. Pharmacol (2003) 463:199–216.
  • HAEFELY W, MARTIN JR, SCHOCH P: Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Li. (1990) 11:452–456.
  • •Detailed discussion of the potential advantages of BZ site partial agonists compared to full agonists.
  • COSTA E, GUIDOTTI A: Benzodiazepines on trial: a research strategy for their rehabilitation. Trends Pharmacol Li. (1996) 17:192–200.
  • ATACK JR: Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site. Curr. Drug Targets - CNS Neurol Disorders (2003) 2:213–232.
  • GIUSTI P, DUCIC I, PUIA G et al: Imidazenil: A new partial positive allosteric modulator of y-aminobutyric acid (GABA) action at GABAA receptors. J. Pharmacol Expt. Therap. (1993) 266:1018–1028.
  • COSTA E: From GABAA receptor diversity emerges a unified vision of GABAergic inhibition. AMU. Rev Pharmacol Toxicol (1998) 38:321–350.
  • JENSEN ML, TIMMERMANN DB, VARMING T, JOHANSEN TH, AHRING PK: Two distinct actions of the novel anxiolytic compound NS 2710 on GABAA receptors. Soc. Neurosci. Abstr. (2001) 491:8.
  • MIRZA NR, NIELSEN EO, JOHANSEN TH et al: N52664: An atypical benzodiazepine site ligand. 2003 Abstract Viewer/Itinerary Planner. Society for Neuroscience Washington DC. (2003) 959:8.
  • SMITH AJ, ALDER L, SILK J et al: Effect of a subunit on allosteric modulation of ion channel function in stably expressed human recombinant y-aminobutyric acidA receptors determined using 36C1 ion flux. Mot. Pharmacol (2001) 59:1108–1118.
  • FLECK MW: Molecular actions of (V-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone. Pharmacol Exp. Therap. (2002) 302:612–618.
  • CARLSON JN, HASKEW R, WACKER J, MAISONNEUVE IM, GLICK SD, JERUSSI TP: Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite. Eur.j Pharmacol (2001) 415:181–189.
  • McMAHON LR, JERUSSI TP, FRANCE CP: Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys. Psychopharmacol (2003) 165:222–228.
  • DUBINSKY B, VAIDYA AH, ROSENTHAL DI et al: 5-Ethoxymethy1-7-fluoro-3-oxo-1,2,3,5- tetrahydrobenzo, 5Iimidazo [1, 2a]pyridine -4-N-(2-fluoropheny6carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic. I Pharmacol Expt. Therap. (2002) 303:777–790.
  • GARDNER CR, DEACON R, GUY AP, MANN G, BUDHRAM P, MILLER P: RU 32698, a new benzodiazepine receptor ligand with anxiolytic but little sedative/ myorelaxant properties. BE J. Pharmacol (1987) 92:537P.
  • ADIS: Y 23684. Drugs R D (1999) 2:68–69.
  • ZONG WZ, WILLIAMS MG, BRANSTETTER DG: Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate. Curr. Drug Metab. (2000) 1:243–254.
  • ULRICH RG, BACON JA, BRANSTETTER DG et al.: Induction of a hepatic toxic syndrome in the Dutch-belted rabbit by a quinoxalinone anxiolytic. Toxicology (1995) 98:187–198.
  • ULRICH RG, BACON JA, BRASS EP, CRAMER CT, PETRELA DK, SUN EL: Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon. Chem. Biol. Interact. (2001) 134.251–270.
  • VAN STEVENINCK AL, GIESCHKE R, SCHOEMAKER RC et al.: Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. BE J. Clia PharmacoL (1996) 41:565–573.
  • DELINI-STULA A, BERDAH-TORDJMAN D: Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia-a study group report. Psychiatr. Res. (1996) 30:239–250.
  • EVANS SM, FOLTIN RW, LEVIN FR, FISCHMAN MW: Behavioral and subjective effects of DN-2327 (pazinaclone) and alprazolam in normal volunteers. Behav. Pharmacol (1995) 6:176–186.
  • LINDEN M, HADLER D, HOFMAN S: Randomised, double-blind, placebo-controlled trial of the efficacy and tolerability of a new isoindoline derivative (DN-2327) in generalized anxiety. Hum. Psychopharmacol Clia Exper. (1997) 12:445–452.
  • MUMFORD GK, RUSH CR, GRIFFITHS RR: Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. ./. Pharmacol Expt. Therap. (1995) 272:570–80.
  • LYDIARD RB, BALLENGER JC, RICKELS K: A double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Abecarnil Work Group. J. Clin. Psychiatry (1997) 58\(Suppl. 11):11–18.
  • POLLACK MH, WORTHINGTON JJ, MANFRO GG, OTTO MW, ZUCKER BG: Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. I Clin. Psychiatry (1997) 58\(Suppl. 11):19–23.
  • AUFDEMBRINKE B: Abecarnil, a new 13-carboline, in the treatment of anxiety disorders. Br. J. Psychiatry (1998) 173\(Suppl. 34):55–63.
  • RICKELS K, DeMARTINIS N, AUFDEMBRINKE B: A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. J. Psychopharmacol (2000) 20:12–18.
  • QUIRK K, BLURTON P, FLETCHER S et al: PHIL-655,708, A novel ligand selective for the benzodiazepine site of GABAA receptors which contain the a5 subunit. Neuropharmacology (1996) 35:1331–1335.
  • SKOLNICK P, HU RJ, COOK CM et al:PHIRY 80: A high-affinity, selective ligand for y-aminobutyric acidA receptors containing a5-subunits. I Pharmacol Exp. Therap. (1997) 283:488–493.
  • MARTIN IL, LATTMAN E: Benzodiazepine recognition site ligands and GABAA receptors. Expert Opin. Ther. Patents (1999) 9:1347–1358.
  • COOKE AJ, HAMILTON NM: a-Subunit selective modulators of GABAA receptor function as CNS therapeutics. Expert Opin. Ther. Patents (2002) 2:1491–1501.
  • COLLINS IJ, MOYES CR, DAVEY WB et al.: 3-Heteroary1-2-pyridones: Benzodiazepine site agonists with functional selectivity for a2/a3-subtypes of human GABAA receptor-ion channels. I Med. Chem. (2002) 45:1887–1900.
  • CHAMBERS MS, ATACK JR, BROMIDGE FA et al: 6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABAA a5 receptor inverse agonists. [Med. Chem. (2002) 45:1176–1179.
  • CHAMBERS MS, ATACK JR, BROUGHTON HB et al: Identification of a novel, selective GABAA a5 receptor inverse agonist which enhances cognition. J. Med. Chem. (2003) 46:2227–2240.
  • SZEKERES HJ, ATACK JR, CHAMBERS MS et al: 3,4- Dihydronaphthalen-1 (2H)-ones: novel ligands for the benzodiazepine site of a5-containing GABAA receptors. Bioorg. Med. Chem. Lett. (2004) 14:2871–2875.
  • JOHNSTONE TB, HOGENKEMP DJ, COYNE L et al.: Modifying quinolone antibiotics yields new anxiolytics. Nature Med. (2004) 10:31–32.
  • MIRZA NR, SANDAGER NIELSEN K, HARTZ B, MATHIESON L, AHRING PK: An in-vivo method for differentiating subtype-selective and non-selective GABAA receptor positive modulators. FENS Abstr. (2004) 2:A164:13.
  • ROWLETT JK, PLATT DM, LELAS S, ATACK JR, DAWSON GR: Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc. Natl. Acad. Sci. USA (2005) 102:915–920.
  • •Confirmation that the non-sedating anxiolytic properties of L-838417 initially observed in rodents extends to primates.
  • ROSTOCK A, TOBER C, DOST R et al: AWD-131-138. Drugs Future (1998) 23:253–255.
  • MEALY NE, BAYES M: Treatment of psychiatric disorders. Drugs Fut. (2004) 29:923–977.
  • GRIEBEL G, PERRAULT G, SIMIAND J et at: SL651498: an anxioselective compound with functional selectivity for a2- and a3-containing y-aminobutyric acidA (GABAA) receptors. J. Phannacol Expt. Therap. (2001) 298:753–768.
  • GRIEBEL G, PERRAULT G, SIMIAND J et al: SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for Generalized Anxiety Disorder and muscle spasms. CNS Drug Rev. (2003) 9:3–20.
  • DOBLE A, CANTON T, DRIESLER S, PIOT 0 et al: RP 59037 and RP 60503: anxiolytic cyclopyrrolone derivatives with low sedative potential. interaction with the y-aminobutyric acidA/benzodiazepine receptor complex and behavioral effects in the rodent. I Phannacol Exp. Therap. (1993) 266:1213–1226.
  • BATESON A: Pagoclone Indevus. Curr. Opin. Investig. Drugs (2003) 4:91–95.
  • ATACK JR, PIKE A, MARSHALL G et al: The in vivo properties of pagoclone in rat are mediated by the hydroxylated metabolite. 2004 Abstract viewer/Itinerary Planner, Society for Neuroscience, Washington D.C. (2004) 844:9.
  • LINGFORD-HUGHES AR, UHL N, FEENEY AJ et al.: Is pagoclone a partial agonist at the central GABA-benzodiazepine receptor: a PIC] flumazenil positron emission tomography study? Int. Neuropsychopharmacol. (2000) 3\(Suppl. 1):5288.
  • SANDFORD JJ, FORSHALL S, BELL C et al Crossover trial of pagoclone and placebo in patients with DSM-IV panic disorder. J. Psychophannacol (2001) 15:205–208.
  • SORBERA LA, LEESON PA, SILVESTRE J, CASTANER J: Pagoclone. Drugs Fut. (2001) 26:651–657.
  • KAVOUSSI RJ, PANDE AC, LYDIARD RB, PAPP L, PIGOTT TA, RICKELS K: Efficacy and safety of pagoclone, a novel GABA modulator in the treatment of panic disorder with or without agoraphobia. Int. I Neuropsychophannacol (2000) 3\(Suppl. 1):5280.
  • VANOVER KE, ZHANG L, BARRETT JE: Discriminative stimulus and anxiolytic-like effects of the novel compound CL 273,547. Exp. Chit Psychophannacol (1994) 2:223–233.
  • KOSTAKIS EE, GRAVIELLE MC, SKOLNICK P et al.: Subtype selective modulation of GABAA receptor by ocinaplon, an anxioselective pyrazolopyrimidine. Abstract Viewer/ Itinerary Planner. Sono, for Neuroscience, 2003, Washington DC (2003) 48.3.
  • BEER B, CZOBOR P, LIPPA A, PETTI S, SKOLNICK P, STARK J: Efficacy of Ocinaplon, a novel GABAA receptor modulator, in Generalized Anxiety Disorder. Abstract Viewer/Itinerary Planner. Society for Neuroscience, 2002, Washington DC (2002) 396:15.
  • CHILMAN-BLAIR K, CASTANER J, SILVESTRE JS: Ocinaplon. Drugs Future (2003) 28:115–120.
  • CZOBOR P, STARK J, BEER G et al: A double-blind, placebo controlled study of DOV 273,547 (ocinaplon) in the treatment of generalized anxiety disorder (GAD). Abstract Viewer/Itinerary Planner. Society for Neuroscience, 2003, Washington DC (2003) 959.12.
  • LEWIS DA, VOLK DW, HASHIMOTO T: Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychophannacology (Berl.) (2004) 174:143–150.

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  • http://www.Dovpharm.com DOV Press release, November 23 2004.

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