MF-8, a novel promising arylpiperazine-hydantoin based 5-HT 7 receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation

Latacz, Gniewomir; Lubelska, Annamaria; Jastrzębska-Więsek, Magdalena; Partyka, Anna; Kucwaj-Brysz, Katarzyna; Wesołowska, Anna; Kieć‐Kononowicz, Katarzyna; Handzlik, Jadwiga

doi:10.1016/j.bmcl.2018.02.003

Cited by 38 publications

(61 citation statements)

References 30 publications

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“…The affinity to P-glycoprotein test was performed as described previously [22,[35][36][37] by using commercial the Pgp-Glo TM Assay System (Promega, Madison, WI, USA), accordingly to the manufacturer's protocol. The reactions were prepared in triplicate in white polystyrene, flat-bottom Nunc TM MicroWell TM 96-well microplates (Thermo Scientific, Waltham, MA USA).…”

Section: Affinity To P-glycoproteinmentioning

confidence: 99%

“…The metabolic stability assays were performed as described in our previous articles [22,[35][36][37]. The pharmacokinetic parameters of compounds were estimated by using human liver microsomes (HLMs) (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Metabolic Stabilitymentioning

confidence: 99%

“…The study was performed using the CYP3A4 P450-Glo TM and CYP2D6 P450-Glo TM commercial tests provided by Promega (Madison, WI, USA). The influence of compounds on CYPs activity was tested in white polystyrene, flat-bottom Nunc TM MicroWell TM 96-well microplates (Thermo Scientific, Waltham, MA USA), and the bioluminescence signal was measured with a microplate reader (EnSpire) in luminescence mode, as described previously [22,[35][36][37]. KMP-10 and DJ-18 were tested in triplicate in the range of 0.01-25 µM for both isoforms' P450 cytochrome.…”

Section: Drug-drug Interaction (Ddi)mentioning

confidence: 99%

“…The mutagenic activity was assessed by using the Ames MPF (Microplate Format Mutagenicity) Assay [22,[36][37][38] provided by Xenometrix AG (Allschwill, Switzerland), with the use of bacteria Salmonella typhimurium strain TA100, thus enabling the detection of base-pair substitution. The growth of reverted bacteria in 384-well plates was observed after 72 h of incubation at 37 • C throughout the change of the color of the indicator medium from purple to yellow.…”

Section: Ames Testmentioning

confidence: 99%

“…Hepatotoxicity was estimated using the hepatoma HepG2 (ATCC ® HB-8065 TM ) cell line according to previously described protocols [22,[35][36][37]. The CellTiter 96 ® AQueous Non-Radioactive Cell Proliferation Assay was obtained from Promega (Madison, WI, USA).…”

Section: Hepatotoxicity Assaymentioning

confidence: 99%

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Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

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Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

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Section: Affinity To P-glycoproteinmentioning

confidence: 99%

Section: Metabolic Stabilitymentioning

confidence: 99%

Section: Drug-drug Interaction (Ddi)mentioning

confidence: 99%

Section: Ames Testmentioning

confidence: 99%

Section: Hepatotoxicity Assaymentioning

confidence: 99%

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Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

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Novel, Dual Target‐Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B

et al. 2020

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Annelated purinedione derivatives have been shown to act as possible multiple‐target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido‐ and diazepino[2,1‐f]purinedione derivatives were designed as dual‐target‐directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO‐B. This allowed 9‐(2‐chloro‐6‐fluorobenzyl)‐3‐ethyl‐1‐methyl‐6,7,8,9‐tetrahydropyrimido[2,1‐f]purine‐2,4(1H,3H)‐dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO‐B: 243 nM) to be identified as the most potent dual‐acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure‐activity relationships was complemented by molecular‐docking studies based on previously published X‐ray structures of the protein targets. Such dual‐acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO‐B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease

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Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

et al. 2021

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MF-8, a novel promising arylpiperazine-hydantoin based 5-HT 7 receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation

Cited by 38 publications

References 30 publications

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

Novel, Dual Target‐Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B

Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

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