Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

Abstract GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative a...

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Autores principales:	Joerg F. Hipp, Frederic Knoflach, Robert Comley, Theresa M. Ballard, Michael Honer, Gerhard Trube, Rodolfo Gasser, Eric Prinssen, Tanya L. Wallace, Andreas Rothfuss, Henner Knust, Sian Lennon-Chrimes, Michael Derks, Darren Bentley, Lisa Squassante, Stephane Nave, Jana Nöldeke, Christoph Wandel, Andrew W. Thomas, Maria-Clemencia Hernandez
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cc826ca236941e185deaad9d64c993b
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spelling	oai:doaj.org-article:1cc826ca236941e185deaad9d64c993b2021-12-02T18:15:25ZBasmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man10.1038/s41598-021-87307-72045-2322https://doaj.org/article/1cc826ca236941e185deaad9d64c993b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87307-7https://doaj.org/toc/2045-2322Abstract GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.Joerg F. HippFrederic KnoflachRobert ComleyTheresa M. BallardMichael HonerGerhard TrubeRodolfo GasserEric PrinssenTanya L. WallaceAndreas RothfussHenner KnustSian Lennon-ChrimesMichael DerksDarren BentleyLisa SquassanteStephane NaveJana NöldekeChristoph WandelAndrew W. ThomasMaria-Clemencia HernandezNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joerg F. Hipp Frederic Knoflach Robert Comley Theresa M. Ballard Michael Honer Gerhard Trube Rodolfo Gasser Eric Prinssen Tanya L. Wallace Andreas Rothfuss Henner Knust Sian Lennon-Chrimes Michael Derks Darren Bentley Lisa Squassante Stephane Nave Jana Nöldeke Christoph Wandel Andrew W. Thomas Maria-Clemencia Hernandez Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
description	Abstract GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.
format	article
author	Joerg F. Hipp Frederic Knoflach Robert Comley Theresa M. Ballard Michael Honer Gerhard Trube Rodolfo Gasser Eric Prinssen Tanya L. Wallace Andreas Rothfuss Henner Knust Sian Lennon-Chrimes Michael Derks Darren Bentley Lisa Squassante Stephane Nave Jana Nöldeke Christoph Wandel Andrew W. Thomas Maria-Clemencia Hernandez
author_facet	Joerg F. Hipp Frederic Knoflach Robert Comley Theresa M. Ballard Michael Honer Gerhard Trube Rodolfo Gasser Eric Prinssen Tanya L. Wallace Andreas Rothfuss Henner Knust Sian Lennon-Chrimes Michael Derks Darren Bentley Lisa Squassante Stephane Nave Jana Nöldeke Christoph Wandel Andrew W. Thomas Maria-Clemencia Hernandez
author_sort	Joerg F. Hipp
title	Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
title_short	Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
title_full	Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
title_fullStr	Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
title_full_unstemmed	Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
title_sort	basmisanil, a highly selective gabaa-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1cc826ca236941e185deaad9d64c993b
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Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

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