title: A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential.
abstract: Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABAA α5 receptors that has promising drug-like properties and warrants further development.
authors.affiliation: Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Ling
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Mihalik
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, Dundee, Scotland, UK.
authors.forename: Lori-An
authors.initials: LA
authors.lastname: Etherington
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Kapus
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Pálvölgyi
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Gigler
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Kertész
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Gaál
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Pallagi
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Kiricsi
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Szabó
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Papp
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: László G
authors.initials: LG
authors.lastname: Hársing
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Lévay
authors.affiliation: Institut de Recherches Servier, Croissy-sur-Seine, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, Dundee, Scotland, UK.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, Dundee, Scotland, UK.
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.affiliation: Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Barkóczy
authors.affiliation: Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Volk
authors.affiliation: Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Simig
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Gacsályi
authors.affiliation: Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary. Electronic address: ferenc.antoni@egis.hu.
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Antoni
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058787:GABA-A Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010433:Pentylenetetrazole; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000927:Anticonvulsants; D058787:GABA-A Receptor Antagonists; C527986:GABRA5 protein, human; C496250:Gabra5 protein, mouse; C511535:Gabra5 protein, rat; D018697:Nootropic Agents; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010433:Pentylenetetrazole
keywords: 2,3-Benzodiazepine; Benzothiophene; Extrasynaptic receptors; GABA; GABA(A) antagonist; Isoquinoline; Nootropic agents; Object recognition test