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GABAA Receptor Subtype- and Function-Selective Ligands: Key Issues in Translation to Humans

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GABAA Receptor Subtype- and Function-Selective Ligands: Key Issues in Translation to Humans 1521-0081/70/4/836–878$35.00 https://doi.org/10.1124/pr.117.014449 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:836–878, October 2018 Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans Werner Sieghart and Miroslav M. Savic Center for Brain Research, Medical University of Vienna, Vienna, Austria (W.S.) and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (M.M.S.) Abstract ....................................................................................838 I. Introduction . ..............................................................................838 A. g-Aminobutyric Acid Type A Receptors and Their Heterogeneity.........................838 B. g-Aminobutyric Acid Type A Receptor Structure and Pharmacology. ...................839 C. Aim of the Present Review. ............................................................840 II. Receptor Subtype-selective Binding Versus Subtype-selective Efficacy........................841 Downloaded from III. Receptor Subtype-selective Efficacy—Dependence on the Conditions of Measurements. .......841 IV. Importance of Concentration-response Relationships of “Receptor Subtype-selective Ligands”....................................................................................842 A. Referring Compound Actions to that of Standard Benzodiazepines Distorts Original Data ...................................................................................842 by guest on July 30, 2019 B. Maximal Efficacy Hides a Possible Subtype Selectivity at Lower Concentrations . .......843 C. Concentration of Compounds Eliciting In Vivo Effects ...................................843 V. Currently Available Compounds Claimed to Be g-Aminobutyric Acid Type A Receptor Subtype-Selective . ........................................................................843 A. Subtype-Selectivity Claimed for Incompletely Investigated Compounds ..................843 B. Compounds Claimed to Selectively Modulate a1bg2 Receptors . .........................844 1. Zolpidem............................................................................844 2. Indiplon ............................................................................845 3. Zaleplon, Zopiclone ..................................................................845 4. b-CCt . ..............................................................................846 5. Ro15-1788 (Flumazenil) . ............................................................846 C. Compounds Claimed to Selectively Modulate a2bg2, a3bg2, and a5bg2 Receptors. .......846 1. L-838,417 . ........................................................................847 2. TPA-023B. ........................................................................847 3. NS11394, NS16085..................................................................847 D. Compounds Claimed to Selectively Modulate a2bg2 and a3bg2 Receptors. .............848 1. Compound 4 ........................................................................848 2. Pyridazine Series of a2bg2- and a3bg2-selective Compounds .........................848 3. SL-651,498. ........................................................................848 4. TPA023 .............................................................................848 5. MRK-409 . ........................................................................849 6. SH-053-29-N (HZ166), MP-III-024, KRM-II-81. .....................................850 7. Baicalin.............................................................................851 8. 6-Hydroxyflavone . ..................................................................851 Address correspondence to: Werner Sieghart, Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. E-mail: [email protected] In part, financial support was provided by the Ministry of Education, Science and Technological Development, R. Serbia – Grant No. 175076 (MMS). https://doi.org/10.1124/pr.117.014449. 836 GABAA Receptor Subtype- and Function-selective Ligands 837 9. Fa131. ..............................................................................851 10. AZD7325............................................................................851 E. Compounds Claimed to Selectively Modulate a3bg2 Receptors . .........................852 1. TP003 ..............................................................................852 2. YT-III-31............................................................................853 3. a3IA................................................................................853 F. Compounds Claimed to Selectively Modulate a5bg2 Receptors . .........................853 1. SH-053-R-CH3-29F, MP-III-022 ......................................................854 2. a5IA................................................................................854 3. a5IA-II .............................................................................854 4. MRK-016 . ........................................................................855 5. L-655,708 . ........................................................................855 6. PWZ-029............................................................................856 7. RY-024 .............................................................................856 8. RO4938581 . ........................................................................856 9. TB21007 ............................................................................857 10. S44819. .............................................................................857 11. XLi-093 .............................................................................857 G. Compounds Preferentially Modulating a4bg2 and/or a6bg2 Receptors ...................858 1. CMD-45.............................................................................858 2. XHe-III-74 . ........................................................................858 3. PZ-II-029 (Compound 6), LAU159, LAU463 ..........................................859 4. (+)ROD188. ........................................................................859 5. Amiloride . ........................................................................860 6. Furosemide . ........................................................................860 H. Benzodiazepine Site Antagonist Actions . ................................................860 I. Compounds Claimed to Selectively Modulate b1-containing GABAA Receptors ...........861 1. Salicylidene Salicylhydrazide . ......................................................861 2. Fragrant Dioxane Derivatives . ......................................................861 3. Pyrazoloquinolinones ................................................................862 J. Compounds Claimed to Selectively Modulate b2/3-containing GABAA Receptors. .......863 1. Loreclezole, Etomidate, and Others . ................................................863 2. Etifoxine and Polyacetylene Compounds . ..........................................864 3. b2/3-Selective Enaminones (Compound 2-261) . .....................................864 4. Function of b2orb3 Subunit-containing GABAA Receptors. .........................864 K. Compounds Claimed To Modulate Selectively d-Containing GABAA Receptors............864 1. g-Aminobutyric Acid Site Ligands . ................................................865 a. THIP (gaboxadol) ................................................................865 b. Thio-4-PIOL . ..................................................................865 c. Thio-THIP .......................................................................865 d. GABA site antagonists ...........................................................865 2. Neurosteroids and Tracazolate ......................................................866 3. Ketamine . ........................................................................866 4. DS2.................................................................................866 5. Methaqualone.......................................................................866 L. Compounds Modulating g1- or g3-Containing GABAA Receptors .........................867 M. Compounds Modulating «-, u-, or p-Containing GABAA Receptors........................867 N. Compounds Modulating r-Containing GABAA Receptors . ...............................868 VI. Discrepancy between the In Vivo Effects of Drugs in Rodent and Human Studies ............868 A. Receptors Containing b1-Subunits Might Contribute to the Sedative Action of Benzodiazepine Site Ligands............................................................869 B. Receptors Containing g1org3 Subunits, or Those Containing a4, a6, or d Subunits, Might Contribute to the In Vivo Effects of Benzodiazepine Site Ligands .................870 ABBREVIATIONS: DBI, diazepam binding inhibitor; GABA, g-aminobutyric acid; GABAA-receptor, GABA type A receptor; GABAB- receptor, GABA type B receptor; KCC2, K+-Cl2 cotransporter 2; NKCC1, Na+-K+-2Cl2 cotransporter 1; TSPO, translocator protein (18 kDa). 838 Sieghart and Savic C. Additional Interaction with Targets Different from GABAA Receptors Could Also Contribute to the Separation of Anxiolytic and Sedative Properties of Ligands ...........870 D. A
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