The development of GABAergic drugs is an active area of research in the fields of medicinal chemistry and neurodegenerative disease. The concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain is estimated to be approximately 1000-times the levels of the classical monoamine neurotransmitters. More than one third of brain neurons use GABA for synaptic communication and the concentration of brain GABA essentially controls the mental and, to a large extent, the physical health of humans. GABA has been implicated in a large number of human disease states, which include: anxiety and stress disorders, musculoskeletal and pain disorders, insomnia and sleep disorders, addiction and drug-withdrawal syndromes, epilepsy and seizures, anesthesia, liver diseases and hepatic encephalopathy, cognition, learning and memory disorders, premenstrual and other hormonal disorders and numerous other related conditions. In light of the ubiquitous importance of GABA to our health, we brought together several experts in the field for this special focus issue, for which it has been our pleasure and privilege to act as Guest Editors.
A cursory glance at this issue’s content will provide a hint of the wide range of current research in the area of GABA chemistry. The issue comprises coverage of the synthesis, neurobiology and biological evaluation of GABAergic molecules. We greatly appreciate the contributions of all the authors.
In this issue
Wei-Yang Lu’s commentary on the potential use of GABAergic drugs in the treatment of asthma reveals the potential of GABAergic molecules in treating disease states other than those listed earlier Citation[1]. Miledi et al. explore the evidence indicating that changes in GABAergic neurotransmission are involved in the pathology of Alzheimer’s disease, and the related potential pharmacological implications Citation[2].
We are delighted that one of the leading experts in GABA research, Wolfgang Froestl, has contributed the issue’s lead article, an historical perspective on GABAergic drugs covering over half a century of research Citation[3]. It presents a captivating account of progress in the field during that timeframe. Kulig and Salat review GABA uptake inhibitors as targets for the treatment of several GABAergic diseases Citation[4]. This article gives guidance for the development of novel GAT inhibitors as a potential future source of efficacious anticonvulsants, anxiolytics and antidepressant agents. Schousboe et al. provide a mini-review of the current status of GABA transport inhibitors in seizure protection and provide future perspectives of non-GAT1 inhibitors as anticonvulsants Citation[5]. On a related theme, Mula outlines the current and future perspectives and clinical status of GABAergic antiepileptic drugs Citation[6].
Partially fluorinated natural and unnatural molecules have been utilized extensively in medicinal chemistry. O‘Hagan reviews the synthesis of enantiomers of 3-fluoro-GABA and discusses how comparative analysis of these enantiomers has been used to assess the conformation of GABA binding to GABAA and the GABA-metabolizing enzyme, GABA transaminase Citation[7]. Ganem et al. describe the synthesis of small-molecule GABAergic molecules Citation[8]. The preliminary communication from the Ramachandran group describes the synthesis of novel GABA derivatives for potential GABA pharmacological studies Citation[9]. Shubina and co-workers provide an overview of the synthetic routes to, and properties of carbocyclic (cyclopropanes, cyclobutanes and cyclohexanes) and cage (adamantane and others) hydrocarbons – analogs of GABA with conformationally rigid carbon skeletons Citation[10]. Finally, although a relatively new topic, this issue also features an extensive review by Chebib of GABAC receptor pharmacology and its implications for myopia, learning and memory Citation[11].
We very much hope that readers will find this issue timely and informative!
Acknowledgements
We are grateful for the interest shown by Iwao Ojima, Senior Editor of Future Medicinal Chemistry and thank the in-house editorial and production teams for their support in bringing this issue together.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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Bibliography
- Lu W -Y. The potential use of GABAergic drugs in the treatment of asthma. Future Med. Chem.3(2), 145–147 (2011).
- Limon A , Reyes-RuizJM, MilediR. GABAergic drugs and Alzheimer’s disease.Future Med. Chem.3(2), 149–153 (2011).
- Froestl W . An historical perspective on GABAergic drugs.Future Med. Chem.3(2), 163–175 (2011).
- Salat K , KuligK. GABA transporters as targets for new drugs.Future Med. Chem.3(2), 211–222 (2011).
- Schousboe A , MadsenKK, WhiteHS. GABA transport inhibitors and seizure protection: the past and future.Future Med. Chem.3(2), 183–187 (2011).
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