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Rational approaches for the design of various GABA modulators and their clinical progression

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Abstract

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer’s disease, Huntington’s chorea, migraine, Parkinson’s disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure–activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

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Abbreviations

AC:

American cockroach

AMH:

3-Acetylamino-4′-O-methylhonokiol

Arg:

Arginine

AUC:

Area under the curve

bbsP2C:

Bovine brain stem cells

BDC:

Bile duct-cannulated

BDZ:

Benzodiazepines

bfcP2B:

Brain frontal cortex cells

BGT:

GABA uptake protein

BMI:

Body mass index

C188:

Cysteine

CBR:

Central Benzodiazepines receptors

CC:

Common cutworm

CHO:

Chinese hamster ovary

Cmax:

Maximum concentration

CNS:

Central nervous system

D162:

Aspartic acid

DMCM:

Methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate

DMSO:

Dimethyl sulfoxide

EBOB:

4-Ethynyl-4-n-propylbicycloorthobenzoate

EC50 :

50% Effective concentration

ED50 :

Effective dose

FLIPR:

Fluorometric imaging plate reader

FMP:

Fluorometric membrane potential

Fe:

Ferrocene

GABA:

Gamma-aminobutyric acid

GABAA-R:

GABA-A receptors

GABA-AT:

GABA-amino transferase

GABACls:

GABA-induced chloride current

GAT:

GABA transporters

GB:

GABA binding

GHB:

Gamma-hydroxybutyric acid

GIRK:

G-protein-activated inwardly rectifying

Glu:

Glutamic acid

GluCls:

Glutamate–gated chloride channels

HEK293:

Human embryonic kidney cells

HPMC:

Hydroxypropylmethylcellulose

i.v.:

Intravenous

IC50 :

50% Inhibitory concentration

ID/g:

Injected dose per gram

IGABA-max :

Maximal GABA-induced chloride current modulation

log D:

Lipophilic parameter

log P:

Lipophilic parameter

mGABA:

Mammalian GABA

mGAT:

Mammalian GABA transferase

MH:

4′-O-methylhonokiol

nAChRs:

Nicotinic acetylcholine receptors

NAM:

Negative allosteric modulation

nM:

Nanomolar

OA:

Open arm

PAM:

Positive allosteric modulation

PET:

Positron emission tomography

Phe:

Phenylalanine

po:

Per os (by mouth)

PTZ:

Pentylenetetrazole

RDL:

Resistance to dieldrin

SAR:

Structure–activity relationship

SBP:

Small brown plant

Ser:

Serine

SIH:

Stress-induced hyperthermia

SMD:

Steered molecular dynamics

SPV:

Saccadic peak velocity

STZ:

Streptozotocin

TBPS:

Tert-butylbicyclophosphorothionates

Thr:

Threonine

TPMPA:

Tetrahydropyridine-4-yl-methyl-phosphinic acid

Tyr:

Tyrosine

References

  1. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) International union of pharmacology. XV. Subtypes of γ-Aminobutyric AcidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50:291–314

    CAS  PubMed  Google Scholar 

  2. Bonnert TP, Mckernan RM, Farrar S, Bourdelles BL, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJS, Brown N, Wafford KA, Whiting PJ (1999) θ, a novel γ-aminobutyric acid type A receptor subunit. Proc Natl Acad Sci USA 96:9891–9896

    CAS  PubMed  Google Scholar 

  3. Tolman JA, Faulkner MA (2009) Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval. Expert Opin Pharmacother 10:3077–3089

    CAS  PubMed  Google Scholar 

  4. Bormann J (2000) The ‘ABC’ of GABA receptors. Trends Pharmacol Sci 21:16–19

    CAS  PubMed  Google Scholar 

  5. Ando H, Kawaai K, Bonneau B, Mikoshiba K (2018) Remodeling of Ca2 + signaling in cancer: regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors. Adv Biol Regul 68:64–76

    CAS  PubMed  Google Scholar 

  6. Burt DR, Kamatchi GL (1991) GABAA receptor subtypes: from pharmacology to molecular biology. FASEB J 5:2916–2923

    CAS  PubMed  Google Scholar 

  7. Davies PA, Hanna MC, Hales TG, Kirkness EF (1997) Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit. Nature 385:820–823

    CAS  PubMed  Google Scholar 

  8. Whiting PJ, Mcallister G, Vassilatis D, Bonnert TP, Heavens RP, Smith DW, Hewson L, O’Donnell R, Rigby MR, Sirinathsinghji DJS, Marshall G, Thompson SA, Wafford KA (1997) Neuronally restricted RNA splicing regulates the expression of a novel GABAA receptor subunit conferring atypical functional properties. J Neurosci 17:5027–5037

    CAS  PubMed  PubMed Central  Google Scholar 

  9. (a) Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C (2007) GABA A/Bz receptor subtypes as targets for selective drugs, Curr Med Chem 14:2680–2701; (b) Mckernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19:139–143; (c) Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update Pharmacol Rev 60:243–260

  10. (a) Michałowski MA, Kraszewskic S, Mozrzymas JW (2017) Binding site opening by loop C shift and chloride ion-pore interaction in the GABAA receptor model. Phys Chem Chem Phys 19:13664; (b) Mehta AK, Ticku MK (1999) An update on GABAA receptors. Brain Res Rev 29:196–217; (c) Johnston GAR (2005) GABA(A) receptor channel pharmacology. Curr Pharm Design 11:1867–1885

  11. Howell O, Atack JR, Dewar D, Mckernan RM, Sur C (2000) Density and pharmacology of alpha5 subunit-containing GABA(A) receptors are preserved in hippocampus of Alzheimer’s disease patients. Neuroscience 98:669–675

    CAS  PubMed  Google Scholar 

  12. (a) Richard WO (2018) GABAA receptor: positive and negative allosteric modulators. Neuropharmacology 136:10–22; (b) Achermann G, Ballard TM, Blasco F, Broutin PE, Buttelmann B, Fischer H, Graf M, Hernandez MC, Hilty P, Knoflach F, Koblet A, Knust H, Kurt A, Martin JR, Masciadri R, Porter RHP, Stadler H, Thomas AW, Trube G, Wichmann J (2009) Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABAA α5 inverse agonist series. Bioorg Med Chem Lett 19:5746–5752

  13. (a) Korpi ER, Matilla MJ, Wisden W, Luddens H (1997) GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med 29:275–282; (b) Atack JR (2003) Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2:213–232

  14. Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acid A receptor subtypes. Pharmacol Rev 47:181–234

    CAS  PubMed  Google Scholar 

  15. Mattner F, Mardon K, Loc’h C, Katsifis A (2006), Pharmacological evaluation of an [(123)I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors. Life Sci 79:287–294

    CAS  PubMed  Google Scholar 

  16. George CFP (2001) Pyrazolopyrimidines. The Lancet 358:1623–1626

    CAS  Google Scholar 

  17. Falco JL, Lloveras M, Buira I, Teixido J, Borrell JI, Mendez E, Terencio J, Palomer A, Guglietta A (2005) Design, synthesis and biological activity of acyl substituted 3-amino-5-methyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones as potential hypnotic drugs. Eur J Med Chem 40:1179–1187

    CAS  PubMed  Google Scholar 

  18. Lader MH (1999) Limitations on the use of Benzodiazepines in anxiety and insomnia: are they justified? Eur Neuropsychopharmacol 9:399–405

    Google Scholar 

  19. Ashton H, Haddad P, Dursun S, Deakin B (2004) Adverse syndromes and psychiatric drugs: a clinical guide. Oxford University Press, Oxford

    Google Scholar 

  20. Pin JP, Kniazeff J, Binet V, Liu J, Maurel D, Galvez T, Duthey B, Havlickova M, Blahos J, Prezeau L, Rondard P (2004) Activation mechanism of the heterodimeric GABAB receptor. Biochem Pharmacol 68:1565–1572

    CAS  PubMed  Google Scholar 

  21. Galvez T, Duthey B, Kniazeff J, Blahos J, Rovelli G, Bettler B, Prezeau L, Pin JP (2001) Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. EMBO J 20:2152–2159

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kniazeff J, Galvez T, Labesse G, Pin JP (2002) No ligand binding in the GB2 subunit of the GABAB receptor is required for activation and allosteric interaction between the subunits. J Neurosci 22:7352–7361

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bettler B, Tiao JYH (2006) Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol Ther 110:533–543

    CAS  PubMed  Google Scholar 

  24. Amin J, Weiss DS (1994) Homomeric rho 1 GABA channels: activation properties and domains. Recept Channels 3:227–326

    Google Scholar 

  25. Polenzani L, Woodward RM, Miledi R (1991) Expression of mammalian γ-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes. Proc Natl Acad Sci USA 88:4318–4322

    CAS  PubMed  Google Scholar 

  26. Shimada S, Cutting G, Uhl GR (1992) Gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid F1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes. Mol Pharmacol 41:683–687

    CAS  PubMed  Google Scholar 

  27. Drew CA, Johnston GAR, Weatherby RP (1984) Bicuculline insensitive GABA receptors: studies on the binding of (-)-baclofen to rat cerebellar membranes. Neurosci Lett 52:317–321

    CAS  PubMed  Google Scholar 

  28. Rozzo A, Armellin M, Franzot J, Chiaruttini C, Nistri A, Tongiorgi E (2002) Expression and dendritic mRNA localization of GABAC receptor F1 and F2 subunits in developing rat brain and spinal cord. Eur J Neurosci 15:1747–1758

    PubMed  Google Scholar 

  29. Enz R, Brandstaetter JH, Waessle H, Bormann J (1996) Immunocytochemical localization of the GABAC receptor F subunits in the mammalian retina. J Neurosci 16:4479–4490

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ge S, Goh ELK, Sailor KA, Kitabatake Y, Ming G, Song H (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593

    CAS  PubMed  Google Scholar 

  31. Liu B, Hattori N, Jiang B, Nakayama Y, Zhang NY, Wu B, Kitagawa K, Taketo M, Matsuda H, Inagaki C (2004) Single cell RTPCR demonstrates differential expression of GABAC receptor F subunits in rat hippocampal pyramidal and granule cells. Mol Brain Res 123:1–6

    CAS  PubMed  Google Scholar 

  32. Boue-Grabot E, Roudbaraki M, Bascles L, Tramu G, Bloch B, Garret M (1998) Expression of GABA receptor F subunits in rat brain. J Neurochem 70:899–907

    CAS  PubMed  Google Scholar 

  33. Chang L, Christine CC, Ernst T (2003) Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders. J Clin Psychiatry 64:7–14

    CAS  PubMed  Google Scholar 

  34. Guastella J, Nelson NN, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306

    CAS  PubMed  Google Scholar 

  35. Liu QR, Lopez-Corcuera B, Mandiyan S, Nelson H, Nelson N (1993) Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain. J Biol Chem 268:2106–2112

    CAS  PubMed  Google Scholar 

  36. Nelson H, Mandiyan S, Nelson N (1990) Cloning of the human brain GABA transporter. FEBS Lett 269:181–184

    CAS  PubMed  Google Scholar 

  37. Borden LA, Smith KE, Hartig PR, Branchek TA, Weinshank RL (1992) Molecular heterogeneity of the gamma-aminobutyric acid (GABA) transport system. Cloning of two novel high affinity GABA transporters from rat brain. J. Biol. Chem. 267:21098–21104

    CAS  PubMed  Google Scholar 

  38. Borden LA, Dhar TGM, Smith KE, Branchek TA, Weinshank RL, Cluchowski C (1994) Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Recept Channels 2:207–213

    CAS  PubMed  Google Scholar 

  39. Yamauchi A, Uchida S, Kwon HM, Preston AS, Robey RB, Garcia-Perez A, Burg MB, Handler JS (1992) Cloning of a Na(+)- and Cl(-)-dependent betaine transporter that is regulated by hypertonicity. J Biol Chem 267:649–652

    CAS  PubMed  Google Scholar 

  40. Borden LA, Smith KE, Gustafson EL, Branchek TA, Weinshank RL (1995) Cloning and expression of a betaine/GABA transporter from human brain. J Neurochem 64:977–984

    CAS  PubMed  Google Scholar 

  41. Lopez-Corcuera B, Liu QR, Mandiyan S, Nelson H, Nelson N (1992) Expression of a mouse brain cDNA encoding novel gamma-aminobutyric acid transporter. J Biol Chem 267:17491–17493

    CAS  PubMed  Google Scholar 

  42. (a) Lehre AC, Rowley NM, Zhou Y, Holmseth S, Guo C, Holen T, Hua R, Laake P, Olofsson AM, Poblete-Naredo I, Rusakov DA, Madsen KK, Clausen RP, Schousboe A, White HS, Danbolt NC (2011) Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice, Epilepsy Res 98:70–81. (b) Søren S, Laurent D, Olivier T, Flemming SJ (2012) A steered molecular dynamics study of binding and translocation processes in the GABA transporter, PLoS ONE 7:e39360

  43. Zhou Y, Holmseth S, Guo C, Hassel B, Hofner G, Huitfeldt HS, Wanner KT, Danbolt NC (2012) Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. J Biol Chem 287:35733–35746

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Deguchi T, Yoshimoto M, Ohba R, Ueda S (2000) Antimutagenicity of the purple pigment, hordeumin, from uncooked barley bran-fermented broth. Biosci Biotechnol Biochem 64:414–416

    CAS  PubMed  Google Scholar 

  45. Meiers S, Kemeny M, Weyand U, Gastpar R, Von Angerer E, Moarko DJ (2001) The anthocyanidins cyanidin and delphinidin are potent inhibitors of the epidermal growth-factor receptor. Agric Food Chem 49:958–962

    CAS  Google Scholar 

  46. George TG, Richard J, Barscz T, Capers J, Werbovetz KA (2008) Flavylium salts as precursors of biologically active chalcones. Lett Drugs Des Discov 5:69–73

    CAS  Google Scholar 

  47. Kueny-Stotz M, Chassaing S, Brouillard R, Nielsen M, Goeldner M (2008) Flavylium salts as in vitro precursors of potent ligands to brain GABA-A receptors. Bioorg Med Chem Lett 18:4864–4867

    CAS  PubMed  Google Scholar 

  48. (a) Hess GP, Goldner M, Givens R (2005) In Dynamic studies in biology: phototriggers, photoswitches and caged biomolecules. Wiley, New York, Chapter 4.3; (b) Hess GP (2003) Frontiers in drug design and discovery, volume 1, Biophys Chem 100:493–506

  49. Shembekar VR, Chen Y, Carpenter BK, Hess GP (2005) A protecting group for carboxylic acids that can be photolyzed by visible light. Biochemistry 44:7107–7114

    CAS  PubMed  Google Scholar 

  50. Shembekar VR, Carpenter BK, Ramakrishnan L, Hess GP (2004) Polym. Preprints, American Chemical Society, Division of Polymer Chemistry, vol 45, p 893

  51. Fan L, Lewis RW, Hess GP, Ganem B (2009) A new synthesis of caged GABA compounds for studying GABAA receptors. Bioorg Med Chem Lett 19:3932–3933

    CAS  PubMed  Google Scholar 

  52. Hall BJ, Chebib M, Hanrahan JR, Johnston GAR (2004) Flumazenil-independent positive modulation of γ-aminobutyric acid action by 6-methylflavone at human recombinant α1β2γ2L and α1β2 GABAA receptors. Eur J Pharmacol 491:1–8

    CAS  PubMed  Google Scholar 

  53. Hanrahan JR, Chebib M, Johnston GAR (2011) Flavonoid modulation of GABAA receptors. Br J Pharmacol 163:234–245

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mewett KN, Fernandez SP, Pasricha AK, Devenish APSO, Hibbs DE, Chebib M, Johnston GAR, Hanrahan JR (2009) Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors. Bioorg Med Chem 17:156–7173

    Google Scholar 

  55. Crockett S, Baur R, Kunert O, Belaj F, Sigel E (2016) A new chromanone derivative isolated from Hypericum lissophloeus (Hypericaceae) potentiates GABAA receptor currents in a subunit specific fashion. Bioorg Med Chem 24:681–685

    CAS  PubMed  Google Scholar 

  56. Bowery NG, Collins JF, Hill RG (1976) Bicyclic phosphorus esters that are potent convulsants and GABA antagonists. Nature 261:601–603

    CAS  PubMed  Google Scholar 

  57. Korenaga S, Ito Y, Ozoe Y, Eto M (1977) The effects of bicyclic phosphate esters on the invertebrate and vertebrate neuro-muscular junctions. Comp Biochem Physiol C 57:95–100

    CAS  PubMed  Google Scholar 

  58. Squires RF, Casida JE, Richardson M, Saederup E (1983) [35S]t-butylbicyclophosphorothionate binds with high affinity to brain-specific sites coupled to gamma-aminobutyric acid-A and ion recognition sites. Mol Pharmacol 23:326–336

    CAS  PubMed  Google Scholar 

  59. Ozoe Y, Eto M, Clark JM, Matsumura F (1986) Membrane receptors and enzymes as targets of insecticidal action. Plenum Press, New York

    Google Scholar 

  60. Ju XL, Ozoe Y (1999) Bayesian decision theoretic designs for phase II clinical trials with multiple outcomes. Pestic Sci 55:971–977

    CAS  Google Scholar 

  61. Jukk XL, Fusazaki S, Hishinuma H, Qiao X, Ikeda HI, Ozoe Y (2010) Synthesis and structure-activity relationship analysis of bicyclophosphorothionate blockers with selectivity for housefly gamma-aminobutyric acid receptor channels. Pest Manag Sci 66:1002–1010

    Google Scholar 

  62. (a) Akiyoshi Y, Ju XL, Furutani S, Matsuda K, Ozoe Y (2013) Electrophysiological evidence for 4-isobutyl-3-isopropylbicyclophosphorothionate as a selective blocker of insect GABA-gated chloride channels. Bioorg Med Chem Lett 23:3373–3376. (b) Coaviche-Yoval A, Luna H, Tovar-Miranda R, Soriano-Ursúa MA, Trujillo-Ferrara JG (2019) Synthesis and biological evaluation of novel 2,3-disubstituted benzofuran analogues of GABA as neurotropic agents. Med Chem 15:77–86

  63. Costanzo A, Guerrini G, Ciciani G, Bruni F, Selleri S, Costa B, Martini C, Lucacchini A, Malmberg-Aiello P, Ipponi A (1999) Benzodiazepine receptor ligands. 4. Synthesis and pharmacological evaluation of 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides. J Med Chem 42:2218–2226

    CAS  PubMed  Google Scholar 

  64. Sullivan SK, Petroski RE, Verge G, Gross RS, Foster AC, Grigoriadis DE (2004) Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor. J Pharmacol Exp Ther 311:537–546

    CAS  PubMed  Google Scholar 

  65. Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC (2006) Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther 317:369–377

    CAS  PubMed  Google Scholar 

  66. Lippa AS, Czobor P, Stark J, Beer B, Kostakis E, Gravielle M, Bandypadhyay S, Russek SJ, Gibbs TT, Farb DH, Skolnick P (2005) Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator. PNAS 102:7380–7385

    CAS  PubMed  Google Scholar 

  67. Basile AS, Lippa AS, Skolnick P (2006) GABAA receptor modulators as anxioselective anxiolytics. Drug Discov Today Ther. Strateg 3:475–481

    Google Scholar 

  68. Whiting PJ (2006) GABA-A receptors: a viable target for novel anxiolytics. Curr Opin Pharmacol 6:24–29

    CAS  PubMed  Google Scholar 

  69. Ebert B, Wafford KA, Deacon S (2006) Treating insomnia Current and investigational pharmacological approaches. Pharmacol Ther 112:612–629

    CAS  PubMed  Google Scholar 

  70. Ebert B, Wafford KA (2006) Benzodiazepine receptor agonists and insomnia is subtype selectivity lost in translation. Drug Discov Today Ther Strateg 3:547–554

    Google Scholar 

  71. Hoepping A, Scheunemann M, Fischer S, Conrad WD, Hiller A, Wegner F, Diekers M, Steinbach J, Brust P (2007) Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative-hypnotic agent indiplon. Nucl Med Biol 34:559–570

    CAS  PubMed  Google Scholar 

  72. Guerrini G, Ciciani G, Cambi G, Bruni F, Selleri S, Melani F, Montali M, Martini C, Ghelardini C, Norcinid M, Costanzo A (2008) Novel 3-aroylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: synthesis, pharmacological and molecular modeling studies. Bioorg Med Chem 16:4471–4489

    CAS  PubMed  Google Scholar 

  73. Zanzonico P (2004) Positron emission tomography a review of basic principles scanner design and performance and current systems. Semin Nucl Med 34:87–111

    PubMed  Google Scholar 

  74. Hoepping A, Diekers M, Conrad WD, Scheunemann M, Fischer S, Hiller A, Wegner F, Steinbach J, Brust P (2008) Synthesis of fluorine substituted pyrazolopyrimidines as potential leads for the development of PET-imaging agents for the GABAA receptors. Bioorg Med Chem 16:1184–1194

    CAS  PubMed  Google Scholar 

  75. Costanzo A, Guerrini G, Ciciani G, Bruni F, Costagli C, Selleri S, Besnard F, Costa B, Martini C, Aiello PM (2002) Benzodiazepine receptor ligands 7 Synthesis and pharmacological evaluation of new 3-esters of the 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide. 3-(2-Thienylmethoxycarbonyl) derivative an anxioselective agent in rodents. J Med Chem 45:5710–5720

    CAS  PubMed  Google Scholar 

  76. Guerrini G, Ciciani G, Cambi G, Bruni F, Selleri S, Guarino C, Melani F, Montali M, Martini C, Ghelardini C, Norcini M, Costanzo A (2009) Synthesis, in vivo evaluation, and molecular modeling studies of new pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide derivatives and Identification of a bifunctional hydrogen bond area related to the inverse agonism. J Med Chem 52:4668–4682

    CAS  PubMed  Google Scholar 

  77. Guerrini G, Ciciani G, Bruni F, Selleri S, Guarino C, Melani F, Montali M, Daniele S, Martini C, Ghelardini C, Norcini M, Ciattini S, Costanzo A (2010) New Fluoro Derivatives of the Pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide system evaluation of fluorine binding properties in the benzodiazepine site on γ-Aminobutyrric Acid Type A (GABAA) receptor design, synthesis, biological, and molecular modeling investigation. J Med Chem 53:7532–7548

    CAS  PubMed  Google Scholar 

  78. Guerrini G, Ciciani G, Bruni F, Selleri S, Martini C, Daniele S, Ghelardini C, Di Cesare Mannelli L, Costanzo A (2011) Development of ligands at γ-aminobutyrric acid type A (GABAA) receptor subtype as new agents for pain relief. Bioorg Med Chem 97:441–7452

    Google Scholar 

  79. Mitchinson A, Atack JR, Blurton P, Carling RW, Castro JL, Curley KS, Russell MGN, Marshall G, Mckernan RM, Moore KW, Narquizian R, Smith A, Street LJ, Thompson SA, Wafford K (2004) 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones, functionally selective benzodiazepine binding site ligands on the GABAA receptor. Bioorg Med Chem Lett 14:3441–3444

    CAS  PubMed  Google Scholar 

  80. Hintermann S, Hurth K, Nozulak J, Blomley MT, Aichholz R, Blanz J, Kaupmann K, Mosbacher J (2011) Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor. Bioorg Med Chem Lett 21:1523–1526

    CAS  PubMed  Google Scholar 

  81. Guerrini G, Ciciani G, Costanzo A, Daniele S, Martini C, Ghelardini C, Cesare Mannelli LD, Ciattini S (2013) Synthesis of novel cognition enhancers with pyrazolo[5,1-c][1,2,4]benzotriazine core acting at γ-aminobutyric acid type A (GABA(A)) receptor. Bioorg Med Chem 21:2186–2198

    CAS  PubMed  Google Scholar 

  82. Kahnberg P, Howard M, Liljefors T, Nielsen M, Qstergaard Nielsen E, Sterner O, Pettersson I (2004) The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABAA receptor. J Mol Gr. Model 23:253–261

    CAS  Google Scholar 

  83. Lager E, Andersson EP, Nilsson J, Pettersson I, Qstergaard Nielsen E, Nielsen M, Sterner O, Liljefors T (2006) 4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors synthesis, pharmacology, and pharmacophore modeling. J Med Chem 49:2526–2533

    CAS  PubMed  Google Scholar 

  84. Lager E, Nilsson J, Qstergaard Nielsen E, Nielsen M, Liljefors T, Sterner O (2008) Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABA(A) receptors. Bioorgan Med Chem 16:6936–6948

    CAS  Google Scholar 

  85. Dekermendijan K, Kahnberg P, Witt M, Sterner O, Nielsen M, Liljefors T (1999) Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J Med Chem 42:4343–4350

    Google Scholar 

  86. Nilsson J, Qstergaard Nielsen E, Liljefors T, Nielsen M, Sterner O (2008) Azaflavones compared to flavones as ligands to the benzodiazepine binding site of brain GABA(A) receptors. Bioorg Med Chem Lett 18:5713–5716

    CAS  PubMed  Google Scholar 

  87. Xiaodong F, Fang Chang LH, Schmiesing RJ, Steven S, Wesolowski S, Katharine L, Knappenberger L, Jeffrey J, Arriza MC (2010) Developing dual functional allosteric modulators of GABA(A) receptors. Bioorg Med Chem 18:8374–8382

    Google Scholar 

  88. Campbell JB, Warawa EJ (1987) Eur Patent Appl 9:87303949

    Google Scholar 

  89. (a) Patel JB, Meiners BA, Salama AI, Malick JB, Resch JF, U’Pritchard DC, Giles RE, Hesp B, Goldberg ME (1990) Prog Clin Biol Res 361 (Curr. Future Trends Anticonvulsant, Anxiety, Stroke Ther.):483; (b) Resch JF (1987) Ger. (East) Patent DD: 249011; (c) Resch JF (1989) European Patent Application 89300865:6

  90. Alhambra C, Becker C, Blake T, Chang A Jr, Damewood JR, Daniels T, Dembofsky BT, Gurley DA, Hall JE, Herzog KJ, Horchler CL, Ohnmacht CJ, Schmiesing RJ, Dudley A, Ribadeneira MD, Knappenberger KS, Maciag C, Stein MM, Chopra M, Liu XF, Christian EP, Arriza JL, Chapdelaine MJ (2011) Bioorg Med Chem 19:2927–2938

    CAS  PubMed  Google Scholar 

  91. Chang HF, Chapdelaine MJ, Dembofsky BT, Herzog KJ, Horchler C, Schmiesing RJ (2008); WO Patent 2008/155572 A2

  92. Moran MD, Wilson AA, Charles SE, Parkes J, Ng A, Sadovski O, Graff A, Daskalakis ZJ, Houle S, Chapdelaine MJ, Vasdev N (2012) Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB-benzodiazepine receptors. Bioorg Med Chem 20:4482–4488

    CAS  PubMed  Google Scholar 

  93. (a) Larsen TO, Frydenvang K, Frisvad JC, Christophersen C (1998) UV-Guided isolation of alantrypinone, a novel Penicillium alkaloid. J Nat Prod 61:1154–1157; (b) Hart DJ, Magomedov NA (1999) Expedient one-pot synthesis of indolo[3,2-c]isoquinolines via a base-promoted N-alkylation/tandem cyclization, Tetrahedron Lett 40:5429–5433. (c) Hart DJ, Magomedov NA (2001) Synthesis of ent-alantrypinone. J Am Chem Soc 123:5892–5899. (d) Kende AS, Fan J, Chen Z (2003) A concise total synthesis of (±)-alantrypinone by a novel hetero-Diels-Alder reaction. Org Lett 5:3205–3208. (e) Chen Z, Fan J, Kende AS (2004) Total synthesis of (±)-alantrypinone by hetero Diels-Alder reaction. J Org Chem 69:79–85

  94. Watanabe T, Arisawa M, Narusuye K, Alam MS, Yamamoto K, Mitomi M, Ozoe Y, Nishida A (2009) Alantrypinone and its derivatives, synthesis and antagonist activity toward insect GABA receptors. Bioorg Med Chem 17:94–110

    CAS  PubMed  Google Scholar 

  95. Frolund B, Jorgensen AT, Tagmose L, Stensbøl TB, Vestergaard HT, Engblom C, Kristiansen U, Sanchez C, Krogsgaard-Larsen P, Liljefors T (2002) Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABAA antagonists, synthesis, pharmacology, and molecular modeling. J Med Chem 45:2454–2468

    CAS  PubMed  Google Scholar 

  96. Bergmann R, Kongsbak K, Sørensen PL, Sander T, Balle T (2013) A unified model of the GABAA receptor comprising agonist and benzodiazepine binding sites. PLoS ONE 8:52323

    Google Scholar 

  97. Sander T, Frølund B, Bruun AT, Ivanov I, McCammon JA, Balle T (2011) New insights into the GABA receptor structure and orthosteric ligand binding, receptor modeling guided by experimental data. Proteins Struct Funct Bioinf 79:1458–1477

    CAS  Google Scholar 

  98. Petersen JG, Bergmann R, Møller HA, Jørgensen CG, Nielsen B, Kehler J, Frydenvang K, Kristensen J, Balle T, Jensen AA, Kristiansen U, Frølund B (2013) Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as g-aminobutyric acid(A) receptor agonists. J Med Chem 56:993–1006

    CAS  PubMed  Google Scholar 

  99. Petersen JG, Sorensen T, Damgaard M, Nielsen B, Jensen AA, Bergmann TBR, Frolund B (2014) Eur J Med Chem 84:404–416

    CAS  PubMed  Google Scholar 

  100. (a) Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (2006) An inverse agonist selective for alpha 5 subunit-containing GABA receptors enhances cognition. J Pharmacol Exp Ther16:1335–1345; (b) Nutt DJ, Besson M, Wilson SJ, Dawson GR, Lingford-Hughes AR (2007) Blockade of alcohol’s amnestic activity in humans by an alpha 5 subtype benzodiazepine receptor inverse agonist. Neuropharmacology 53:810–820

  101. (a) Merschman SA, Rose MJ, Pearce GES, Woolf EJ, Schaefer BH, Huber AC, Musson DG, Petty K, Rush DJ, Varsolona RJ, Matuszewski BK (2005) Characterization of the solubility of a poorly soluble hydroxylated metabolite in human urine and its implications for potential renal toxicity. Pharmazie 60:359–363. (b) Atack JR (2008) GABA(A) receptor subtype-selective efficacy, TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer CNS. Neurosci Ther 14:25–35. (c) Xue L, Lin L, Hsieh JYK, Matuszewski BK (2004) Determination of a selective GABA‐A α5 receptor inverse agonist in human plasma by high‐performance liquid chromatography with tandem mass spectrometric detection. J Liq Chromatogr Rel Technol 27:689–704

  102. Iqbal F, Ellwood R, Mortensen M, Smart TG, Baker JR (2011) Synthesis and evaluation of highly potent GABA(A) receptor antagonists based on gabazine (SR-95531). Bioorg Med Chem Lett 21:4252–4254

    CAS  PubMed  Google Scholar 

  103. Hosie AM, Sattelle DB (1996) Agonist pharmacology of two drosophila GABA receptor splice variants. Br J Pharmacol 119:1577–1585

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Satoh H, Daido H, Nakamura T (2005) Preliminary analysis of the GABA-induced current in cultured CNS neurons of the cutworm moth (Spodoptera litura). Neurosci Lett 381:125–130

    CAS  PubMed  Google Scholar 

  105. Narusuye K, Nakao T, Abe R, Nagatomi Y, Hirase K, Ozoe Y (2007) Molecular cloning of a GABA receptor subunit from Laodelphax striatella (Fallén) and patch clamp analysis of the homo-oligomeric receptors expressed in a Drosophila cell line. Insect Mol Biol 16:723–733

    CAS  PubMed  Google Scholar 

  106. Rahman MM, Akiyoshi Y, Furutani S, Matsuda K, Furuta K, Ikeda I, Ozoe Y (2012) Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA. Bioorg Med Chem 20:5957–5964

    CAS  PubMed  Google Scholar 

  107. Faizi M, Dabirian S, Tajali H, Ahmadi F, Zavareh ER, Shahhosseini S, Tabatabai SA (2015) Novel agonists of benzodiazepine receptors: design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives. Bioorg Med Chem 23:480–487

    CAS  PubMed  Google Scholar 

  108. Larsen PK, Frolund B, Jorgensen FS, Schousboe A (1994) GABAA receptor agonists, partial agonists, and antagonists. Design and therapeutic prospects. J Med Chem 37:2489–2505. (b) Rabe H, Picard R, Uusi-Oukari M, Hevers W, Luddens H, Korpi ER (2000) Coupling between agonist and chloride ionophore sites of the GABA(A) receptor: agonist/antagonist efficacy of 4-PIOL. Eur J Pharmacol409:233–242. (c) Frolund B, Jensen LS, Storustovu SI, Stensbol TB, Ebert B, Kehler J, Larsen PK, Liljefors T (2007) 4-Aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists: synthesis, pharmacology, and structure-activity relationships. J Med Chem 50:1988–1992. (d) Krehan D, Storustovu SI, Liljefors T, Ebert B, Nielsen B, Larsen PK, Frolund B (2006) Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology. J Med Chem 49:1388–1396

  109. Jansen M, Rabe H, Strehle A, Dieler S, Debus F, Dannhardt G, Akabas MH, Luddens H (2008) Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site. J Med Chem 51:4430–4448

    CAS  PubMed  PubMed Central  Google Scholar 

  110. (a) Lahm GP, Patel KM, Pahutski TF, Smith BK (2007) PCT Intl Appl WO 07/075459. Chem Abstr 147:111908. (b) Lahm GP, Long JK, Pahutski TF, Smith BK, Mahaffey MJ, Rauh JR, Cordova D, Smith RM, Barry JD (2010) Presented at the 239th National Meeting of the American Chemical Society: San Francisco, CA, paper AGRO 8

  111. Lahm GP, Cordova D, Barry JD, Pahutski TF, Smith BK, Long JK, Benner EA, Holyoke CW, Joraski K, Xu M, Schroeder ME, Wagerle T, Mahaffey MJ, Smith RM, Tong MH (2013) 4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel. Bioorg Med Chem Lett 23:3001–3006

    CAS  PubMed  Google Scholar 

  112. Mula M, Pini S, Cassano GB (2007) The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol 27:263–272. (b) Jain AK, Vaidya A, Ravichandran V, Kashaw SK, Agrawal RK (2012) Recent developments and biological activities of thiazolidinone derivatives: a review. Bioorg Med Chem 20:3378–3395. (c) Cunico W, Gomes Jr. CRB, Vellasco WT (2008) Chemistry and biological activities of 1,3-Thiazolidin-4-ones. Mini-Rev Org Chem 5:336–344. (d) Verma A, Saraf SK (2008) 4-Thiazolidinone: a biologically active scaffold. Eur J Med Chem 43:897–905

  113. Pejovic A, Deni MS, Stevanovi D, Damljanovi I, Cevi MV, Kostova K, Kirilova MT, Randjelovi P, Stojanovi NM, Bogdanovi GA, Blagojevi P, D’hooghe M, Radulovi NS, Vukicevi RD (2014) Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site. Eur J Med Chem 83:57–73

    CAS  PubMed  Google Scholar 

  114. Liu G, Furuta K, Nakajima H, Ozoe F, Ozoe Y (2014) Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols. Bioorg Med Chem 22:4637–4645

    CAS  PubMed  Google Scholar 

  115. Zeng CM, Manion BD, Benz A, Evers AS, Zorumski CF, Mennerick S, Covey DF (2005) Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3R,5R)- and (3R,5_)-3-hydroxypregnan-20-one. J Med Chem 48:3051–3059

    CAS  PubMed  Google Scholar 

  116. Kasal A, Matyas L, Budesinsky M (2005) Neurosteroid analogues: synthesis of 6-aza-allopregnanolone. Tetrahedron 61:2269–2278

    CAS  Google Scholar 

  117. Sunol C, Garcia DA, Bujons J, Kristofikova Z, Matyas L, Babot Z, Kasal A (2006) Activity of B-nor analogues of neurosteroids on the GABAA receptor in primary neuronal cultures. J Med Chem 49:3225–3234

    CAS  PubMed  Google Scholar 

  118. Nicoletti D, Ghini AA, Furtmuller R, Sieghart W, Dodd RH, Burton G (2000) Synthesis and GABAA receptor activity of 6-oxa-analogs of neurosteroids. Steroids 65:349–356

    CAS  PubMed  Google Scholar 

  119. Scaglione JB, Jastrzebska I, Krishnan K, Li P, Akk G, Manion BD, Benz A, Taylor A, Rath NP, Evers AS, Zorumski CF, Mennerick S, Covey DF (2008) Neurosteroid analogues. 14. Alternative ring system scaffolds: GABA modulatory and anesthetic actions of cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes. J Med Chem 51:1309–1318

    CAS  PubMed  Google Scholar 

  120. Wittmer LL, Hu Y, Kalkbrenner M, Evers AS, Zorumski CF, Covey DF (1996) Enantioselectivity of steroid-induced g-aminobutyric acid A receptor modulation and anesthesia. Mol Pharmacol 50:1581–1586. (b) Covey DF, Nathan D, Kalkbrenner M, Nilsson KR, Hu Y, Zorumski CF, Evers AS (2000) Enantioselectivity of pregnanolone-induced g-aminobutyric acid A receptor modulation and anesthesia. J Pharmacol Exp Ther 293:1009–1016

  121. Anderson A, Boyd AC, Clark JK, Fielding L, Gemmell DK, Hamilton NM, Maidment MS, May V, McGuire R, McPhail P, Sansbury FH, Sundaram H, Taylor R (2000) Conformationally constrained anesthetic steroids that modulate GABAA receptors. J Med Chem 43:4118–4125. (b) Hawkinson JE, Kimbrough CL, Belelli D, Lambert JJ, Purdy RH, Lan C (1994) Correlation of neuroactive steroid modulation of [35S] t-butylbicyclophosphorothionate and [3H] flunitrazepam binding and g-aminobutyric acidA receptor function. Mol Pharmacol 46:977–985

  122. Katona BW, Krishnan K, Cai ZY, Manion BD, Benz A, Taylor A, Evers AS, Zorumski CF, Mennerick S, Covey DF (2008) Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens. Eur J Med Chem 43:107–113

    CAS  PubMed  Google Scholar 

  123. Duran FJ, Leman L, Ghini AA, Burton G, Dauban P, Dodd RH (2002) Intramolecular PhI = O mediated copper-catalyzed aziridination of unsaturated sulfamates: a new direct access to polysubstituted amines from simple homoallylic alcohols. Org Lett 24:2481–2483. (b) Durán FJ, Ghini AA, Dauban P, Dodd RH, Burton G (2005) Synthesis of 6,19-sulfamidate bridged pregnanes. J Org Chem 70:8613–8616. (c) Espino CG, When PM (2001) Chow J, Du Bois J (2001) Synthesis of 1,3-difunctionalized amine derivatives through selective C–H bond oxidation. J Am Chem Soc 123:6935–6936. (d) Slavikova B, Kasal A, Chodounska H, Kristofikova Z (2002) Collect Czech 3α-Fluoro Analogues of “Allopregnanolone” and their binding to GABAA receptors. Chem Commun 67:30–46. (e) Slavikova B, Kasal A, Uhlirova L, Krsiakb M, Chodounska H, Kohout L (2001) Suppressing aggressive behavior with analogs of allopregnanolone (epalon). Steroids 66: 99–105

  124. Duran FJ, Edelsztein VC, Ghini A, Rey M, Coirini H, Dauban P, Dodd RH, Burton G (2009) Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone. Bioorg Med Chem 17:6526–6533

    CAS  PubMed  Google Scholar 

  125. Veleiro AS, Burton G (2009) Structure activity relationships of neuroactive steroids acting on the GABAA receptor. Curr Med Chem 16:455–472

    CAS  PubMed  Google Scholar 

  126. Akk G, Covey DF, Evers AS, Steinbach JH, Zorumski CF, Mennerick S (2007) Mechanisms of neurosteroid interactions with GABAA receptors. Pharmacol Therapeut 116:35–57

    CAS  Google Scholar 

  127. Dansey MV, Chenna PHD, Veleiro AS, Stofíkova ZK, Chodounska H, Kasal A, Burton G (2010) Synthesis and GABAA receptor activity of A-homo analogues of neuroactive steroids. Eur J Med Chem 45:3063–3069

    CAS  PubMed  Google Scholar 

  128. Hogenkamp DJ, Johnstone TBC, Huang JC, Li WY, Tran M, Whittemore ER, Bagnera RE, Gee KW (2007) Enaminone amides as novel orally active GABAA receptor modulators. J Med Chem 50:3369–3379

    CAS  PubMed  Google Scholar 

  129. Cheng J, Ju XL (2010) Homology modeling and atomic level binding study of GABA(A) receptor with novel enaminone amides. Eur J Med Chem 45:3595–3600

    CAS  PubMed  Google Scholar 

  130. Taferner B, Schuehly W, Huefner A, Baburin I, Wiesner K, Ecker GF, Hering S (2011) Modulation of GABAA-receptors by honokiol and derivatives: subtype selectivity and structure-activity relationship. J Med Chem 54:5349–5361

    CAS  PubMed  Google Scholar 

  131. Krishnan K, Manion BD, Taylor A, Bracamontes J, Steinbach JH, Reichert DE, Evers AS, Zorumski CF, Mennerick S, Covey DF (2012) Neurosteroid analogues. 17. Inverted binding orientations of androsterone enantiomers at the steroid potentiation site on γ-aminobutyric acid type A receptors. J Med Chem 55:1334–1345

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Bandi AKR, Lee DU (2011) Chemical Constituents and Bioactivities of Plants from the Genus Pholidota. Chem Biodiver 8:1400–1409

    CAS  Google Scholar 

  133. Yao S, Tang CP, Li XQ, Ye Y, Phochinenins AF (2008) Dimeric 9,10-dihydrophenanthrene derivatives, from Pholidota chinensis. Helv Chim Acta 91:2122–2129

    CAS  Google Scholar 

  134. Majumder PL, Roychowdhury M, Chakraborty S (1998) Thunalbene, a stilbene derivative from the orchid Thunia alba. Phytochemistry 49:2375–2378

    CAS  Google Scholar 

  135. Rueda DC, Schoffmann A, Mieri MD, Raith M, Jahne EA, Hering S, Hamburger M (2014) Identification of dihydrostilbenes in Pholidota chinensis as a new scaffold for GABAA receptor modulators. Bioorg Med Chem 22:1276–1284

    CAS  PubMed  Google Scholar 

  136. Schoffmann A, Wimmer L, Goldmann D, Khom S, Hintersteiner J, Baburin I, Schwarz T, Hintersteininger M, Pakfeifer P, Oufir M, Hamburger M, Erker T, Ecker GF, Mihovilovic MD, Hering S (2014) Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives. J Med Chem 57:5602–5619

    PubMed  PubMed Central  Google Scholar 

  137. (a) Alexeev M, Grosenbaugh DK, Mott DD, Fisher JL (2012) The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology 62:2507. (b) Baur R, Schuehly W, Sigel E (2014) Moderate concentrations of 4-O-methylhonokiol potentiate GABAA receptor currents stronger than honokiol. Biochem Biophys Acta 1840:3017–3021. (c) Maruyama Y, Kuribara H, Morita M, Yuzurihara M, Weintraub STJ (1998) Identification of magnolol and honokiol as anxiolytic agents in extracts of Saiboku-to, an oriental herbal medicine. Nat Prod 61:135. (d) Maruyama Y, Kuribara H (2000) Overview of the pharmacological features of honokiol. CNS Drug Rev 6:35-44

  138. Fuchs A, Baur R, Schoeder C, Sigel E, Muller CE (2014) Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors. Bioorg Med Chem 22:6908–6917

    CAS  PubMed  Google Scholar 

  139. Eltahawy NA, Ibrahim AK, Radwan MM, Zaitone SA, Gomaa M, ElSohly MA, Hassanean HA, Ahmed SA (2015) Mechanism of action of antiepileptic ceramide from Red Sea soft coral Sarcophyton auritum. Bioorg Med Chem Lett 25:5819–5824

    CAS  PubMed  Google Scholar 

  140. (a) Fuchs A, Rempel V, Muller (2013) The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS ONE 8:77739. (b) Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT (2011) Therapeutic applications of compounds in the magnolia family. Pharmacol Ther 130:157–176. (c) Schuehly W, Khan I, Fischer NH (2001) The ethnomedicinal use of magnoliaceae from the southeastern united states as leads in drug discovery. Pharm Biol 39:63–69

  141. Bernaskova M, Schoeffmann A, Schuehly W, Hufner A, Baburin I, Hering S (2015) Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists. Bioorg Med Chem 23:6757–6762

    CAS  PubMed  Google Scholar 

  142. (a) Ma L, Chen J, Wang X, Liang X, Luo Y, Zhu W, Wang T, Peng M, Li S, Jie S, Peng A, Wei Y, Chen L (2011) Structural modification of honokiol, a biphenyl occurring in Magnolia officinalis: the evaluation of honokiol analogues as inhibitors of angiogenesis and for their cytotoxicity and structure-activity relationship. J Med Chem 54:6469–6481. (b) Chen CR, Tan R, Qu WM, Wu Z, Wang Y, Urade Y, Huang ZL, Mangnolol BR (2011) A major bioactive constituent of the bark of Magnolia officinalis, exerts antiepileptic effects via the GABA/benzodiazepine receptor complex in mice. Br J Pharmacol 164:1534–1546. (c) Tripathy S, Chan MH, Chen C (2012) An expedient synthesis of honokiol and its analogues as potential neuropreventive agents. Bioorg Med Chem Lett 22:216–221. (d) Jada S, Doma MR, Singh PP, Kumar S, Malik F, Sharma A, Khan IA, Qazi GN, Kumar HMS (2012) Design and synthesis of novel magnolol derivatives as potential antimicrobial and antiproliferative compounds. Eur J Med Chem 51:35–41. (e) Qu WM, Yue XF, Sun Y, Fan K, Chen CR, Hou YP, Urade Y, Huang ZL (2012) Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice. Br J Pharmacol 167:587–598. (f) Fakhrudin N, Ladurner A, Atanasov AG, Heiss EH, Baumgartner L, Markt P, Schuster D, Ellmerer EP, Wolber G, Rollinger JM, Stuppner H, Dirsch VM (2010) Computer-aided discovery, validation, and mechanistic characterization of novel neolignan activators of peroxisome proliferator-activated receptor gamma. Mol Pharmacol 77:559–566

  143. Rycek L, Puthenkalam R, Schnurch M, Ernst M, Mihovilobvic MD (2015) Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands. Bioorg Med Chem Lett 25:400–403

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Hatanaka Y, Sadakane Y (2002) Photoaffinity labeling in drug discovery and developments: chemical gateway for entering proteomic frontier. Curr Top Med Chem 2:271–288

    CAS  PubMed  Google Scholar 

  145. Karolin J, Johansson LBA, Strandberg L, Ny T (1994) Fluorescence and absorption spectroscopic properties of dipyrrometheneboron difluoride (BODIPY) derivatives in liquids, lipid membranes, and proteins. J Am Chem Soc 116:7801–7806

    CAS  Google Scholar 

  146. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H (1997) Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature 386:239–246

    CAS  PubMed  Google Scholar 

  147. Li X, Cao JH, Li Y, Rondard P, Zhang Y, Yi P, Liu JF, Nan FJ (2008) Activity-based probe for specific photoaffinity labeling gamma-aminobutyric acid B (GABAB) receptors on living cells: design, synthesis, and biological evaluation. J Med Chem 51:3057–3060

    PubMed  Google Scholar 

  148. Smith CR, LaRocca NG, Giesser BS, Scheinberg LC (1991) High-dose oral baclofen: experience in patients with multiple sclerosis. Neurology 41:1829–1831

    CAS  PubMed  Google Scholar 

  149. Tayacke RJ, Lingford A, Reed LJ, Nutt DJ (2010) GABAB receptors in addiction and its treatment. Adv Pharmacol 58:373–396

    Google Scholar 

  150. Lidums I, Lehmann A, Checklin H, Dent J, Holloway RH (2000) Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects. Gastroenterology 118:7–13

    CAS  PubMed  Google Scholar 

  151. Yomiya K, Matsuo N, Tomiyasu S, Yoshimoto T, Tamaki T, Suzuki T, Matoba M (2009) Baclofen as an adjuvant analgesic for cancer pain. J Med Chem 26:112–118

    Google Scholar 

  152. Talyor MC, Bates CP (1979) A double-blind crossover trial of baclofen—a new treatment for the unstable bladder syndrome. J Urol 51:504–505

    Google Scholar 

  153. Queva C, Bremner M, Edlind A, Ekstrand AJ, Elg S, Erickson S, Johansson T, Lehmann A, Msttson JP (2003) Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice. Br J Pharmacol 140:315

    CAS  PubMed  PubMed Central  Google Scholar 

  154. (a) Xu F, Peng G, Phan T, Dilip U, Chen JL, Rogan TC, Zhnag X, Grindstaff K, Annamalai T, Koller K, Gallop MA, Wustrow DJ (2011) Discovery of a novel potent GABA(B) receptor agonist. Bioorg Med Chem Lett 21:6582–6585. (b) Bowery NG (2006) GABA(B) receptor: a site of therapeutic benefit. Curr Opin Pharmacol 6:37–43. (c) Malherbe P, Masciadri1 R, Norcross RD, Knoflach F, Kratzeisen C, Zenner MT, Kolb Y, Marcuz A, Huwyler J, Nakagawa T, Porter RHP, Thomas AW, Wettstein JG, Sleight AJ, Spooren W, Prinssen EP (2008) Characterization of (R,S)-5,7-di-tert-butyl-3- hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors. Br J Pharmacol 154:797–811

  155. Murata Y, Woodward RM, Miledi R, Overman LE (1996) The first selective antagonist for a GABAC receptor. Bioorg Med Chem Lett 6:2073–2076

    CAS  Google Scholar 

  156. Kumar JR, Chebib M, David E, Kim HHL, Grsham AR, Johnston K, Noeris Salam R (2008) Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships. J Med Chem 51:3825–3840

    CAS  PubMed  Google Scholar 

  157. Fuelep GH, Hoesl CE, Hoefner G, Wanner KT (2006) New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids. Euro J Med Chem 41:809–824

    CAS  Google Scholar 

  158. Zhao X, Hoesl CE, Hoefner GC, Wanner KT (2005) Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidine-2-acetic acid. Euro J Med Chem 40:231–238

    CAS  Google Scholar 

  159. Kirch P (2004) Modern fluoroorganic chemistry. Wiley, Weinheim 23:237–271

    Google Scholar 

  160. Kirk KL (2008) Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org Process Res Dev 12:305

    CAS  Google Scholar 

  161. Ojima I (2009) Fluorine in medicinal chemistry and chemical biology. Blackwell Publishing Ltd, West Sussex

    Google Scholar 

  162. Begue JP, Bonnet D (2008) Bioorganic and medicinal chemistry of fluorine. Wiley, Hoboken

    Google Scholar 

  163. Zhuang W, Zhao X, Zhao G, Guo L, Lian Y, Zhou J, Fang D (2009) Synthesis and biological evaluation of 4-fluoroproline and 4-fluoropyrrolidine-2-acetic acid derivatives as new GABA uptake inhibitors. Bioorg Med Chem 17:6540–6546

    CAS  PubMed  Google Scholar 

  164. Zhao X, Pabel J, Hofner G, Wanner T (2013) Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors. Bioorg Med Chem 21:470–484

    CAS  PubMed  Google Scholar 

  165. Steffan T, Renukappa T, Hofner G, Wanner T (2015) Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids. Bioorg Med Chem 23:1284–1306

    CAS  PubMed  Google Scholar 

  166. Croucher MJ, Meldrun BS, Krogagaard P (1983) Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration. Eur J Pharmacol 89:217–228

    CAS  PubMed  Google Scholar 

  167. Yunger LM, Fowler PJ, Zarevics P, Setler PE (1984) Novel inhibitors of gamma-aminobutyric acid (GABA) uptake: anticonvulsant actions in rats and mice. J Pharmacol Exp Ther 228:109–115

    CAS  PubMed  Google Scholar 

  168. Ali FE, Bondinell WE, Dandridge PA, Frazee JS, Garvey E, Girard G, Kaiser C, Ku TW, Lafferty JJ, Moonsammy GI, Oh H, Rush JA, Setler PE, Stringer OD, Venslavsky JW, Volpe BW, Yunger LM, Zirkle CL (1985) Orally active and potent inhibitors of gamma-aminobutyric acid uptake. J Med Chem 28:653–660

    CAS  PubMed  Google Scholar 

  169. Braestrup C, Nielsen EB, Sonnewald U, Knutsen LJS, Anderson KE, Jansen JA, Frederiksen K, Anderson PH, Mortensen A, Suzak PD (1990) (R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid binds with high affinity to the brain gamma-aminobutyric acid uptake carrier. J Neurochem 54:639–647

    CAS  PubMed  Google Scholar 

  170. Nielsen EB, Suzdak P, Anderson KE, Knutsen LJS, Sonnewald U, Braestrup C (1991) Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor. Eur J Pharmacol 196:257–266

    CAS  PubMed  Google Scholar 

  171. Dhar TGM, Borden LA, Tyagarajan S, Smith KE, Brancheck TA, Weinshank RL, Gluchowski C (1994) Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3. J Med Chem 37:2334–2342

    CAS  PubMed  Google Scholar 

  172. Schon F, Kelly JS (1975) Selective uptake of (3H) beta-alanine by glia: association with glial uptake system for GABA. Brain Res 86:243–257

    CAS  PubMed  Google Scholar 

  173. Hog S, Greenwood JR, Madsen KB, Larsson OM, Frolund B, Schousboe A, Krogsgaard P, Clausen RP (2006) Structure-activity relationships of selective GABA uptake inhibitors. Curr Top Med Chem 6:1861–1882

    PubMed  Google Scholar 

  174. Sitka I, Allmendinger L, Fulep G, Hofner G, Wanner KT (2013) Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors. Eur J Med Chem 65:487–499

    CAS  PubMed  Google Scholar 

  175. Hack S, Worlein B, Hofiner G, Pabel J, Wanner KT (2011) Development of imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors. Eur J Med Chem 46:1483–1498

    CAS  PubMed  Google Scholar 

  176. Maitre M (1997) The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog Neurobiol 51:337–361

    CAS  PubMed  Google Scholar 

  177. Crunelli V, Emri Z, Leresche N (2006) Unravelling the brain targets of gamma-hydroxybutyric acid. Curr Opin Pharmacol 6:44–52

    CAS  PubMed  Google Scholar 

  178. Zepperitz C, Hofner G, Wanner KT (2006) MS-binding assays, Kinetic, saturation, and competitive experiments based on quantitation of bound marker as exemplified by the GABA transporter mGAT1. Chem Med Chem 1:208–217

    CAS  PubMed  Google Scholar 

  179. Kulig K, Wieckowski K, Wieckowska A, Gajda J, Pochwat B, Hofner GC, Wanner KT, Malawska B (2011) Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors. Eur J Med Chem 46:183–190

    CAS  PubMed  Google Scholar 

  180. (a) Kowalczyk P, Salat K, Hofner GC, Guzior N, Filipek B, Wanner KT, Kulig K (2013) 2-Substituted 4-hydroxybutanamides as potential inhibitors of the g-aminobutyric acid transporters: mGAT1-mGAT4. Synthesis and biological evaluation. Bioorg Med Chem 21:5154–5167; (b) Salat K, Kulig K (2011) GABA transporters as targets for new drugs. Future Med Chem 3:211–222; (c) Kowalczyk P, Hofner GC, Wanner KT, Kulig K (2012) Synthesis, pharmacological evaluation of new 4,4-diphenylbut-3-enyl derivatives of 4-hydroxybutanamides as GABA uptake inhibitors. Acta Pol Pharm 69:157–160. (d) Salat K, Librowski T, Moniczewski A, Stanisz-Wallis K, Wieckowski K, Malawska B (2012) Analgesic, antioedematous and antioxidant activity of g-butyrolactone derivatives in rodents. Behav Pharmacol 23:407–416

  181. Kowalczyk P, Salat K, Hofner GC, Mucha M, Rapacz A, Podkowa A, Filipek B, Wanner KT, Kulig K (2014) Synthesis, biological evaluation and structure-activity relationship of new GABA uptake inhibitors, derivatives of 4-aminobutanamides. Eur J Med Chem 83:256–273

    CAS  PubMed  Google Scholar 

  182. Nanavati SM, Silverman RB (1991) Mechanisms of inactivation of γ-aminobutyric acid aminotransferase by the antiepilepsy drug γ-vinyl GABA (vigabatrin). J Am Chem Soc 113:9341–9349

    CAS  Google Scholar 

  183. Siverman RB (2012) The 2011 E. B. Hershberg award for important discoveries in medicinally active substances: (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) a GABA aminotransferase inactivator and new treatment for drug addiction and infantile spasms. J Med Chem 55:567–575

    Google Scholar 

  184. (a) Kazuta Y, Matsuda A, Shuto SJ (2002) Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine. J Org Chem 67:1669–1677; (b) Kazuta Y, Hirano K, Natsume K, Yamada S, Kimura R, Matsumoto S, Furuichi K, Matsuda A, Shuto SJ (2003) Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure. J Med Chem 46:1980–1988; (c) Watanabe M, Kazuta Y, Hayashi H, Yamada S, Matsuda A, Shuto S (2006) Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure. J Med Chem 49:5587–5596 (d) Watanbe M, Hirokawa T, Kobayashi T, Yoshida S, Ito Y, Yamada S, Orimoto N, Yamasaki Y, Arisawa M, Shuto S (2010) Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy. J Med Chem 53:3585–3593; (e) Yonezawa S, Yamamoto T, Yamakawa H, Muto C, Hosono M, Hattori K, Higashino K, Yutsudo T, Iwamoto H, Kondo Y, Sakagami M, Togmae H, Tanaka Y, Nakano T, Takemoto H, Arisawa M, Shuto S (2012) Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode. J Med Chem 55:8838–8858; (f) Mizuno A, Miura S, Watanabe M, Ito Y, Yamada S, Odagami T, Kogami Y, Arisawa M, Shuto S (2013) Three-dimensional structural diversity-oriented peptidomimetics based on the cyclopropylic strain. Org Lett 15:1686–1689

  185. Nakada K, Yoshikawa M, Ide S, Suemasa A, Kawamura S, Kobayashi T, Masuda E, Ito Y, Hayakawa W, Katayama T, Yamada S, Arisawa M, Minami M, Shuto S (2013) Cyclopropane-based conformational restriction of GABA by a stereochemical diversity-oriented strategy: identification of an efficient lead for potent inhibitors of GABA transports. Bioorg Med Chem 21:4938–4950

    CAS  PubMed  Google Scholar 

  186. Silverman RB, Invergo B (1986) Mechanism of inactivation of gamma-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. First example of an enamine mechanism for a gamma-amino acid with a partition ratio of0. J Am Chem Soc 25:6817–6820

    CAS  Google Scholar 

  187. Neal MJ, Shah MA (1990) Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina. Br J Pharmacol 100:324–328

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Okumura H, Omote M, Takeshita S (1996) In vitro effects of the novel anti-epileptic agent vigabatrin on alanine aminotransferase and aspartate aminotransferase activities in rat serum. Arzneimittelforschung 46:459–462

    CAS  PubMed  Google Scholar 

  189. Storici P, Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, Silverman RB, Schirmer T (2004) Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5′-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin. J Biol Chem 279:363–373

    CAS  PubMed  Google Scholar 

  190. Juncosac JI, Groves AP, Xia G, Silverman RB (2013) Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin. Bioorg Med Chem 21:903–911

    Google Scholar 

  191. Dawood KM, Abdel-Gawad H, Rageb EA, Ellithey M, Mohamed HA (2006) Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles. Bioorg Med Chem 14:3672–3680

    CAS  PubMed  Google Scholar 

  192. Rajak H, Behera CK, Pawar RS, Singour PK, Kharya MD (2010) A novel series of 2,5-disubstituted 1,3,4-thiadiazoles as potential anticonvulsant agent. Chin Chem Lett 21:1149–1152

    CAS  Google Scholar 

  193. Sadarangani IR, Bhatia S, Amarante D, Lengyel I, Stephani RA (2012) Synthesis, resolution and anticonvulsant activity of chiral N-1′-ethyl, N-3′-(1-phenylethyl)-(R, S)-2′H,3H,5′H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3,5′-trione diastereomers. Bioorg Med Chem Lett 22:2507–2509

    CAS  PubMed  Google Scholar 

  194. Shakya AK, Kamal M, Balaramnavar VM, Bardaweel SK, Naik RR, Saxena AK, Siddiqui HH (2016) Design, Synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant agent. Acta Pharm 66:353–372

    CAS  PubMed  Google Scholar 

  195. (a) Zhou D, Sunzel M, Ribadeneira MD, Smith MA, Desai D, Lin J, Grimm SW (2012) A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator—an in vitro and in vivo comparison. Br J Clin Pharmacol 74:98–108; (b) Chen X, Jacobs G, Kam M, Jaeger J, Lappalainen J, Maruff P, Smith MA, Cros AJ, Cohen A, Gerven J (2014) The central nervous system effects of the partial GABA-Aα2,3-selective receptor modulator AZD7325 in comparison with lorazepam in healthy males. Br J Clin Pharmacol 78:1298–1314; (c) National Institutes of Health, National Center for Advancing Translational Sciences (NCATS), AZD7325. Available from: http://www.ncats.nih.gov/files/ AZD7325.pdf [Last accessed 29 Oct 2014]; (d) Mandrioli R, Mercolini L (2015) Discontinued anxiolytic drugs (2009–2014). Expert Opin Investig Drugs 24:557–573

  196. http://www.clinicaltrials.gov.in. Last accessed 02 Feb 2019

  197. Prescot AP, Miller SR, Ingenito G, Huber RS, Kondo DG, Renshaw PF (2018) In Vivo Detection of CPP-115 Target Engagement in Human Brain. Neuropsychopharmacology. 43:646–654

    CAS  PubMed  Google Scholar 

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  1. Kavita Bhagat, Jatinder V. Singh, and Piyusha P. Pagare contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India

    Kavita Bhagat, Jatinder V. Singh, Nitish Kumar, Anchal Sharma, Gurinder Kaur, Harbinder Singh, Sahil Sharma & Preet Mohinder S. Bedi

  2. Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, 23219, USA

    Piyusha P. Pagare

  3. Program in Chemical Biology, Sloan Kettering Institute, New York, NY, 10065, USA

    Nihar Kinarivala & Sahil Sharma

  4. Department of Cell Biology and Neuroscience, Cell and Development Biology Graduate Program, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Srinivasa Gandu

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Bhagat, K., Singh, J.V., Pagare, P.P. et al. Rational approaches for the design of various GABA modulators and their clinical progression. Mol Divers 25, 551–601 (2021). https://doi.org/10.1007/s11030-020-10068-4

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