GABA Receptor Subtypes: Novel Targets for Novel Medicines
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Advances in Pharmacological Sciences GABAA Receptor Subtypes: Novel Targets for Novel Medicines Guest Editors: Naheed R. Mirza, John Atack, and Keith Wafford GABAA Receptor Subtypes: Novel Targets for Novel Medicines Advances in Pharmacological Sciences GABAA Receptor Subtypes: Novel Targets for Novel Medicines Guest Editors: Naheed R. Mirza, John Atack, and Keith Wafford Copyright © 2012 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Advances in Pharmacological Sciences.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Mahmoud S. Ahmed, USA Steven D. Holladay, USA Alison Oliveto, USA Karim A. Alkadhi, USA Kazuhide Inoue, Japan Berend Olivier, The Netherlands Shehzad Basaria, USA P. J. Kadowitz, USA Abdelwahab Omri, Canada Elizabeth F. Burcher, Australia M. O. Karlsson, Sweden Paola Patrignani, Italy David B. Bylund, USA D. A. Kendall, United Kingdom Nunzio Pomara, USA Thomas K. H. Chang, Canada Ismail Laher, Canada Raymond M. Quock, USA Alex F. Chen, USA E. J D Lee, Singapore Gustavo Rodrigo, Uruguay Chi Hin Cho, Hong Kong Xue-Jun LI, China Marjorie Romkes, USA Neal Davies, USA Chun Guang Li, Australia Todd C. Skaar, USA Thrse Di Paolo-Chnevert, Canada Mustafa F. Lokhandwala, USA Philip E. Thorpe, USA Stephen B. Duffull, New Zealand Yijia Lou, China Ivar von Kugelgen,¨ Germany Douglas Eikenburg, USA RickyY.K.Man,HongKong Er-Qing Wei, China Antonio Ferrer-Montiel, Spain Gerald Mnch, Australia Jason White, Australia Charles P. France, USA Eduardo Munoz, Spain Peter J. Winsauer, USA Ram Ganapathi, USA Mitzi Nagarkatti, USA Owen L. Woodman, Australia Christoph H. Gleiter, Germany Kanji Nakatsu, Canada Robert Gogal, USA Masahiro Oike, Japan Contents GABAA Receptor Subtypes: Novel Targets for Novel Medicines, Naheed R. Mirza, John Atack, and Keith Wafford Volume 2012, Article ID 529861, 2 pages Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?, Christiaan H. Vinkers and Berend Olivier Volume 2012, Article ID 416864, 19 pages Perisynaptic GABA Receptors: The Overzealous Protector, Andrew N. Clarkson Volume 2012, Article ID 708428, 8 pages An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists, Xia Chen, Sanne de Haas, Marieke de Kam, and Joop van Gerven Volume 2012, Article ID 134523, 10 pages A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain, Sarah Nickolls, Hannah Mace, Rebecca Fish, Michelle Edye, Rachel Gurrell, Magnus Ivarsson, Tom Pitcher, Sachi Tanimoto-Mori, Denise Richardson, Catherine Sweatman, Janet Nicholson, Cameron Ward, John Jinks, Christine Bell, Kimberly Young, Huw Rees, Andrew Moss, Ross Kinloch, and Gordon McMurray Volume 2011, Article ID 608912, 12 pages Central and Peripheral GABAA Receptor Regulation of the Heart Rate Depends on the Conscious State of the Animal, Bo Hjorth Bentzen and Morten Grunnet Volume 2011, Article ID 578273, 10 pages Neurosteroid Binding Sites on the GABAA Receptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence, Mary W. Hulin, Russell J. Amato, Johnny R. Porter, Catalin M. Filipeanu, and Peter J. Winsauer Volume 2011, Article ID 926361, 12 pages Chronic Treatment with a Promnesiant GABA-A α5-Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model, J. Braudeau, L. Dauphinot, A. Duchon, A. Loistron, R. H. Dodd, Y. Herault,´ B. Delatour, and M. C. Potier Volume 2011, Article ID 153218, 11 pages Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors, Adam C. Errington, David W. Cope, and Vincenzo Crunelli Volume 2011, Article ID 790590, 12 pages Hindawi Publishing Corporation Advances in Pharmacological Sciences Volume 2012, Article ID 529861, 2 pages doi:10.1155/2012/529861 Editorial GABAA Receptor Subtypes: Novel Targets for Novel Medicines Naheed R. Mirza,1 John Atack,2 and Keith Wafford3 1 Neuro Search A/S, Pederstrupvej 93, 2750 Ballerup, Denmark 2 Johnson & Johnson Pharmaceutical Research and Development, 30 Turnhoutseweg, B-2340 Beerse, Belgium 3 Eli Lilly UK, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK Correspondence should be addressed to Naheed R. Mirza, [email protected] Received 14 December 2011; Accepted 14 December 2011 Copyright © 2012 Naheed R. Mirza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. GABAA receptors are ligand gated ion channels that are receptors [4]. A variety of approaches have been used targeted by drugs with multiple therapeutic applications. to develop a greater understanding of the roles of these Most notably, such drugs include the benzodiazepines, the different subtypes in the physiology and pathophysiology hypnotic Z-drugs (zolpidem, zopiclone, and zaleplon), and of the CNS. These strategies include the generation of the barbiturates. The benzodiazepines rapidly achieved pre- transgenic mouse models that have been used to delineate eminence as minor tranquilizers when they were introduced the functions of different subtypes, and the identification in the 1960s but thereafter lost favour, in a story that of subtype-selective pharmacological compounds that have exemplifies how a “good drug can go bad” [1]. Nevertheless, formed the basis of hypotheses that subtype-selectivity can benzodiazepines remain a mainstay of psychopharmacology lead to therapeutic selectivity (e.g., anxioselective drugs but the decline in their public image is encapsulated by without sedation). A combination of these strategies has the colourful comment of Gorman [2] who stated that resulted in emerging scientific evidence for novel therapeutic “Prescribing benzodiazepines is like watching pornography. applications for subtype-selective drugs (e.g., in neuropathic If you ask a person at random if he watches pornography, pain, autism, schizophrenia, Alzheimer’s disease, and stroke), he will vehemently deny it, but someone must be because and consistent with these various hypotheses clinical data it is a billion dollar a year business. Similarly, if you ask on subtype-selective drugs in human trials indicate a novel a physician if he prescribes Valium or Xanax or Ativan, pharmacology relative to known drugs targeting GABAA he or she will say of course not.... Yet, like pornography, receptors. In this special issue, the articles focus on various benzodiazepine prescriptions generate billions of dollars of aspects of the molecular genetics as well as preclinical and revenue around the world, so somebody must be prescribing clinical pharmacology of GABAA receptors. them”. Recently, there has been a resurgence of interest S. Nickoll’s et al. in his paper focus on the novel in GABAA receptor pharmacology which has formed the therapeutic opportunity afforded by drugs that positively basis for the development of novel modulators of discrete modulate GABAA-α2/α3 receptors selectively as novel anal- populations of this receptor family [3]. gesics without sedation, cognition impairment, or abuse. Over the last 25 years or so considerable advances Testing such compounds in animal models of inflammatory in the molecular biology of GABAA receptors have and neuropathic pain, complemented by in vivo electro- identified multiple subtypes of GABAA receptor. Hence, physiology, they highlight the need for sufficient efficacy GABAA receptors are heteropentameric assemblies of pro- at relevant subtypes of GABAA receptor in addition to teins derived from a family comprising 16 members selectivity. C. Vinkers and B. Olivier explore mechanisms (a1–6, β1–3, γ1–3, δ, ε, θ, π). Despite the enormous number underlying benzodiazepine tolerance and conclude that of theoretical pentameric combinations, thankfully only no unifying underlying mechanisms can be discerned but around 20 configurations have been described in native emphasize that since this is an important therapeutic issue 2 Advances in Pharmacological Sciences with respects to currently marketed GABAergic drugs, it is profile of subtype selective compounds in man mirrors an important area to investigate with respects to emerging preclinical data using transgenic mouse models and subtype- subtype selective compounds. selective tools, indicating that molecular neuroscience can be GABAA-α5 and GABAA-δ receptors are located extrasy- translated to the clinic and guide drug development. naptically, mediate tonic inhibitory neurotransmission in The paper by B. H. Bentzen and M. Grunnet gives the CNS, and have different biophysical, physiological, some insight into the drug development of new chemical and pharmacological properties relative to GABAA-α1/α2/α3 entities, specifically focusing on cardiovascular (CV) safety. receptors which are predominantly synaptically located. J. Clearly many benzodiazepines were registered for clinical Braudeau et al. focus on selective negative modulators use in a regulatory environment considerably different from of GABAA-α5 receptors as a unique cognition enhancing today’s. Therefore, in developing novel subtype-selective