Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Eur J Pharmacol
2016 Nov 15;791:433-443. doi: 10.1016/j.ejphar.2016.09.016.
Show Gene links
Show Anatomy links
Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit.
Stamenić TT
,
Poe MM
,
Rehman S
,
Santrač A
,
Divović B
,
Scholze P
,
Ernst M
,
Cook JM
,
Savić MM
.
???displayArticle.abstract???
We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABAA receptors containing the α5 subunit (α5GABAARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABAA receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200mg/kg), but at the price of activating non-α5 GABAARs as well as the desired α5GABAARs at the highest dose. At the dose of 10mg/kg, which elicits a strong positive modulation of α5GABAARs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABAARs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.
Atack,
GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement.
2011, Pubmed
Atack,
GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement.
2011,
Pubmed
Atack,
GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics.
2010,
Pubmed
Atack,
MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.
2011,
Pubmed
Behlke,
A Pharmacogenetic 'Restriction-of-Function' Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice.
2016,
Pubmed
Bodor,
Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites.
2004,
Pubmed
Botta,
Regulating anxiety with extrasynaptic inhibition.
2015,
Pubmed
Chen,
High-efficiency transformation of mammalian cells by plasmid DNA.
1987,
Pubmed
Cheng,
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.
1973,
Pubmed
Clayton,
A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model.
2015,
Pubmed
Collinson,
Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.
2002,
Pubmed
Crestani,
Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors.
2002,
Pubmed
Dawson,
An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition.
2006,
Pubmed
,
Xenbase
Drexler,
Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states.
2013,
Pubmed
Fischer,
Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure.
2010,
Pubmed
,
Xenbase
Frankowski,
Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy.
2012,
Pubmed
Gallos,
Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling.
2015,
Pubmed
Gill,
A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia.
2011,
Pubmed
Guerrini,
Benzodiazepine receptor ligands: a patent review (2006-2012).
2013,
Pubmed
Knabl,
Reversal of pathological pain through specific spinal GABAA receptor subtypes.
2008,
Pubmed
Koh,
Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment.
2013,
Pubmed
Liederer,
Enzymes involved in the bioconversion of ester-based prodrugs.
2006,
Pubmed
Lijinsky,
Esophageal carcinogenesis in F344 rats by nitrosomethylethylamines substituted in the ethyl group.
1982,
Pubmed
Maubach,
GABA(A) receptor subtype selective cognition enhancers.
2003,
Pubmed
McKernan,
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
2000,
Pubmed
Mendez,
The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study.
2013,
Pubmed
Milić,
The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats.
2012,
Pubmed
Navarro,
Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABA(A) receptors which contain the alpha-5 subunit, in the elevated plus-maze test.
2002,
Pubmed
Obradović,
Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: the approximated activation of receptor subtypes may explain behavioral effects.
2014,
Pubmed
,
Xenbase
Ramerstorfer,
The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.
2010,
Pubmed
Redrobe,
Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats.
2012,
Pubmed
,
Xenbase
Rudolph,
GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism.
2014,
Pubmed
Savić,
The differential role of alpha1- and alpha5-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats.
2009,
Pubmed
Savić,
Novel positive allosteric modulators of GABAA receptors: do subtle differences in activity at alpha1 plus alpha5 versus alpha2 plus alpha3 subunits account for dissimilarities in behavioral effects in rats?
2010,
Pubmed
,
Xenbase
Savić,
Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?
2008,
Pubmed
,
Xenbase
Skolnick,
Anxioselective anxiolytics: on a quest for the Holy Grail.
2012,
Pubmed
Soh,
Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance.
2015,
Pubmed
Soto,
Allosteric modulation of GABA(A) receptor subtypes:effects on visual recognition and visuospatial working memory in rhesus monkeys [corrected].
2013,
Pubmed
Takai,
Hydrolytic profile for ester- or amide-linkage by carboxylesterases pI 5.3 and 4.5 from human liver.
1997,
Pubmed
Weaver,
Tissue/blood and tissue/water partition coefficients for propofol in sheep.
2001,
Pubmed
