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An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

Various α (2,3) subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several α (2,3) subtype selective and nonselectiv...

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Autores principales: Chen, Xia, de Haas, Sanne, de Kam, Marieke, van Gerven, Joop
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273701/
https://www.ncbi.nlm.nih.gov/pubmed/22363345
http://dx.doi.org/10.1155/2012/134523
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author Chen, Xia
de Haas, Sanne
de Kam, Marieke
van Gerven, Joop
author_facet Chen, Xia
de Haas, Sanne
de Kam, Marieke
van Gerven, Joop
author_sort Chen, Xia
collection PubMed
description Various α (2,3) subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several α (2,3) subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three α (2,3)-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one α (1)-selective GABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV-) relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the α (2,3) selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the α (2,3)-selective GABA-A agonists, implying an improved therapeutic window.
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spelling pubmed-32737012012-02-23 An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists Chen, Xia de Haas, Sanne de Kam, Marieke van Gerven, Joop Adv Pharmacol Sci Review Article Various α (2,3) subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several α (2,3) subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three α (2,3)-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one α (1)-selective GABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV-) relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the α (2,3) selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the α (2,3)-selective GABA-A agonists, implying an improved therapeutic window. Hindawi Publishing Corporation 2012 2012-01-29 /pmc/articles/PMC3273701/ /pubmed/22363345 http://dx.doi.org/10.1155/2012/134523 Text en Copyright © 2012 Xia Chen et al. https://creativecommons.org/licenses/by/3.0/ 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.
spellingShingle Review Article
Chen, Xia
de Haas, Sanne
de Kam, Marieke
van Gerven, Joop
An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title_full An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title_fullStr An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title_full_unstemmed An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title_short An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists
title_sort overview of the cns-pharmacodynamic profiles of nonselective and selective gaba agonists
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273701/
https://www.ncbi.nlm.nih.gov/pubmed/22363345
http://dx.doi.org/10.1155/2012/134523
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