391-02-6Relevant articles and documents
Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators
Simeone,Iorio,Siebert,Rehman,Schnürch,Mihovilovic,Ernst
, p. 3167 - 3178 (2019/06/17)
Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.
Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
Knutson, Daniel E.,Kodali, Revathi,Divovi?, Branka,Treven, Marco,Stephen, Michael R.,Zahn, Nicolas M.,Dobri?i?, Vladimir,Huber, Alec T.,Meirelles, Matheus A.,Verma, Ranjit S.,Wimmer, Laurin,Witzigmann, Christopher,Arnold, Leggy A.,Chiou, Lih-Chu,Ernst, Margot,Mihovilovic, Marko D.,Savi?, Miroslav M.,Sieghart, Werner,Cook, James M.
supporting information, p. 2422 - 2446 (2018/03/26)
Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.
Synthesis, characterization and antimicrobial studies of some new trifluoromethyl quinoline-3-carbohydrazide and 1,3,4-oxadiazoles
Garudachari,Isloor, Arun M.,Satyanaraya,Ananda,Fun, Hoong-Kun
, p. 30864 - 30875 (2014/08/05)
The present paper describes the synthesis of two new series of 7-(trifluoromethyl)-4-hydroxy substituted quinoline carbohydrazide derivatives (6a-e and 7a-g) and N-alkyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-7- (trifluoromethyl) quinolin-4-amine derivatives (9a-f). Newly synthesized compounds were characterized by spectral studies. The structure of 9a was evidenced by X-ray crystallographic study. Synthesized compounds were screened for their antibacterial performance against Mycobacterium smegmatis and Pseudomonas aeruginosa. Antifungal activity was also carried out on the fungal stains Candida albicans and Penicillium chrysogenum. Compounds 7a and 9c showed significant antimicrobial activity against all the tested microorganisms. Among all the compounds, 6d and 6e showed the lowest MIC value of 6.25 μg mL -1 against Mycobacterium smegmatis indicating these compounds can be possible future antituberculosis agents. 2014 the Partner Organisations.
