Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator

Autores
Lippa, A.; Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; Gravielle, Maria Clara; Bandyopadhyay, S.; Russek, S. J.; Gibbs, T. T.; Farb, David Howard; Skolnick, P.
Año de publicación
2005
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg kg) in the Vogel ‘‘conflict’’ test. This anticonflict effect is blocked by flumazenil (Ro 15–1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABAA receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180–240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders
Fil: A. Lippa. FACULTAD; Argentina
Fil: P. Czobor. FACULTAD; Argentina
Fil: J. Stark. FACULTAD; Argentina
Fil: B. Beer. FACULTAD; Argentina
Fil: E. Kostakis. FACULTAD; Argentina
Fil: Gravielle, Maria Clara. ININFA; Argentina
Fil: S. Bandyopadhyay. FACULTAD; Argentina
Fil: S. J. Russek. FACULTAD; Argentina
Fil: T. T. Gibbs. FACULTAD; Argentina
Fil: D. H. Farb. FACULTAD; Argentina
Fil: P. Skolnick. FACULTAD; Argentina
Materia
GENERALIZED ANXIETY DISORDER
GABAA RECEPTOR
BENZODIAZEPINES
OCINAPLON
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/102789
Acceder
id CONICETDig_a8d036c4e97d2d2c92d11bfb4c83c186
oai_identifier_str oai:ri.conicet.gov.ar:11336/102789
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Selective anxiolysis produced by ocinaplon, a GABAA receptor modulatorLippa, A.Czobor, P.Stark, J.Beer, B.Kostakis, E.Gravielle, Maria ClaraBandyopadhyay, S.Russek, S. J.Gibbs, T. T.Farb, David HowardSkolnick, P.GENERALIZED ANXIETY DISORDERGABAA RECEPTORBENZODIAZEPINESOCINAPLONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg kg) in the Vogel ‘‘conflict’’ test. This anticonflict effect is blocked by flumazenil (Ro 15–1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABAA receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180–240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disordersFil: A. Lippa. FACULTAD; ArgentinaFil: P. Czobor. FACULTAD; ArgentinaFil: J. Stark. FACULTAD; ArgentinaFil: B. Beer. FACULTAD; ArgentinaFil: E. Kostakis. FACULTAD; ArgentinaFil: Gravielle, Maria Clara. ININFA; ArgentinaFil: S. Bandyopadhyay. FACULTAD; ArgentinaFil: S. J. Russek. FACULTAD; ArgentinaFil: T. T. Gibbs. FACULTAD; ArgentinaFil: D. H. Farb. FACULTAD; ArgentinaFil: P. Skolnick. FACULTAD; ArgentinaNational Academy of Sciences2005-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/102789Lippa, A.; Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; et al.; Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 102; 20; 5-2005; 7380-73850027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.0502579102info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/102/20/7380info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:27Zoai:ri.conicet.gov.ar:11336/102789instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:00:27.594CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
title Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
spellingShingle Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
Lippa, A.
GENERALIZED ANXIETY DISORDER
GABAA RECEPTOR
BENZODIAZEPINES
OCINAPLON
title_short Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
title_full Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
title_fullStr Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
title_full_unstemmed Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
title_sort Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator
dc.creator.none.fl_str_mv Lippa, A.
Czobor, P.
Stark, J.
Beer, B.
Kostakis, E.
Gravielle, Maria Clara
Bandyopadhyay, S.
Russek, S. J.
Gibbs, T. T.
Farb, David Howard
Skolnick, P.
author Lippa, A.
author_facet Lippa, A.
Czobor, P.
Stark, J.
Beer, B.
Kostakis, E.
Gravielle, Maria Clara
Bandyopadhyay, S.
Russek, S. J.
Gibbs, T. T.
Farb, David Howard
Skolnick, P.
author_role author
author2 Czobor, P.
Stark, J.
Beer, B.
Kostakis, E.
Gravielle, Maria Clara
Bandyopadhyay, S.
Russek, S. J.
Gibbs, T. T.
Farb, David Howard
Skolnick, P.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GENERALIZED ANXIETY DISORDER
GABAA RECEPTOR
BENZODIAZEPINES
OCINAPLON
topic GENERALIZED ANXIETY DISORDER
GABAA RECEPTOR
BENZODIAZEPINES
OCINAPLON
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg kg) in the Vogel ‘‘conflict’’ test. This anticonflict effect is blocked by flumazenil (Ro 15–1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABAA receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180–240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders
Fil: A. Lippa. FACULTAD; Argentina
Fil: P. Czobor. FACULTAD; Argentina
Fil: J. Stark. FACULTAD; Argentina
Fil: B. Beer. FACULTAD; Argentina
Fil: E. Kostakis. FACULTAD; Argentina
Fil: Gravielle, Maria Clara. ININFA; Argentina
Fil: S. Bandyopadhyay. FACULTAD; Argentina
Fil: S. J. Russek. FACULTAD; Argentina
Fil: T. T. Gibbs. FACULTAD; Argentina
Fil: D. H. Farb. FACULTAD; Argentina
Fil: P. Skolnick. FACULTAD; Argentina
description Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg kg) in the Vogel ‘‘conflict’’ test. This anticonflict effect is blocked by flumazenil (Ro 15–1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABAA receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180–240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders
publishDate 2005
dc.date.none.fl_str_mv 2005-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/102789
Lippa, A.; Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; et al.; Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 102; 20; 5-2005; 7380-7385
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/102789
identifier_str_mv Lippa, A.; Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; et al.; Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 102; 20; 5-2005; 7380-7385
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.0502579102
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/102/20/7380
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269639052099584
score 13.13397

Publicaciones similares