Document Detail

The GABA(A)-BZR complex as target for the development of anxiolytic drugs.
MedLine Citation:
PMID:  22204488     Owner:  NLM     Status:  Publisher    
Anxiety disorders have been linked to alterations in γ-aminobutyric acid (GABA) neurotransmission. GABA interacts with the ligand-gated ion channels, GABAA receptor (GABAA-R) subtypes, and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain α, β and γ subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The best-characterized binding site is the benzodiazepine (BZ) one, which is located at the α/γ subunit interface. BZs are commonly used in therapy for their effects as anxiolytic, anticonvulsants, myorelaxants and hypnotics. The broad range of pharmacological effects of classical BZs are mediated by the selective activation of different GABAA-R subtypes: the α1 subunit containing BZ receptor (BZ-R) mediates sedation, the α2 and α3 subunit containing BZ-R mediates anxiolysis and myorelaxation, and the α5 subunit containing BZ-R mediates cognitive impairment. Based on the current understanding of the diversity of the GABAA-R family, different approaches have been employed to develop drugs that target the GABAA/BZ-R complex with selective anxiolytic action and improved profiles. In this review, we present current knowledge about the role of the GABAA/BZ-R complex in anxiety disorders, new insights into the molecular biology of the receptor complex, and the importance of this target in the development of new therapeutic agents in anxiety.
Maria Letizia Trincavelli; Eleonora Da Pozzob; Simona Daniele; Claudia Martini
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-1
Journal Detail:
Title:  Current topics in medicinal chemistry     Volume:  -     ISSN:  1873-4294     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2011-12-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101119673     Medline TA:  Curr Top Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology. Via Bonanno, 6. 56126 Pisa, Italy.
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