Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice
The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological cha...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Moreira, Lorrane Kelle da Silva [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022transfer abstract |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer - Choi, Seung Hee ELSEVIER, 2021, an international journal, Amsterdam |
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| Übergeordnetes Werk: |
volume:417 ; year:2022 ; day:24 ; month:01 ; pages:0 |
| Links: |
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| DOI / URN: |
10.1016/j.bbr.2021.113582 |
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ELV055761542 |
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| 245 | 1 | 0 | |a Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice |
| 264 | 1 | |c 2022transfer abstract | |
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| 520 | |a The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. | ||
| 520 | |a The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. | ||
| 650 | 7 | |a Piperazine ring |2 Elsevier | |
| 650 | 7 | |a 5-HT1A |2 Elsevier | |
| 650 | 7 | |a Depression |2 Elsevier | |
| 650 | 7 | |a Anxiety |2 Elsevier | |
| 650 | 7 | |a Central nervous system disorders |2 Elsevier | |
| 700 | 1 | |a Silva, Rafaela Ribeiro |4 oth | |
| 700 | 1 | |a da Silva, Dayane Moreira |4 oth | |
| 700 | 1 | |a Mendes, Mirella Andrade Silva |4 oth | |
| 700 | 1 | |a de Brito, Adriane Ferreira |4 oth | |
| 700 | 1 | |a de Carvalho, Flávio Souza |4 oth | |
| 700 | 1 | |a Sanz, Germán |4 oth | |
| 700 | 1 | |a Rodrigues, Marcella Ferreira |4 oth | |
| 700 | 1 | |a da Silva, Artur Christian Garcia |4 oth | |
| 700 | 1 | |a Thomaz, Douglas Vieira |4 oth | |
| 700 | 1 | |a de Oliveira, Valéria |4 oth | |
| 700 | 1 | |a Vaz, Boniek Gontijo |4 oth | |
| 700 | 1 | |a Lião, Luciano Morais |4 oth | |
| 700 | 1 | |a Valadares, Marize Campos |4 oth | |
| 700 | 1 | |a Gil, Eric de Souza |4 oth | |
| 700 | 1 | |a Costa, Elson Alves |4 oth | |
| 700 | 1 | |a Noël, François |4 oth | |
| 700 | 1 | |a Menegatti, Ricardo |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier |a Choi, Seung Hee ELSEVIER |t Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer |d 2021 |d an international journal |g Amsterdam |w (DE-627)ELV006146201 |
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10.1016/j.bbr.2021.113582 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001570.pica (DE-627)ELV055761542 (ELSEVIER)S0166-4328(21)00470-8 DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 35.70 bkl 42.12 bkl Moreira, Lorrane Kelle da Silva verfasserin aut Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. Piperazine ring Elsevier 5-HT1A Elsevier Depression Elsevier Anxiety Elsevier Central nervous system disorders Elsevier Silva, Rafaela Ribeiro oth da Silva, Dayane Moreira oth Mendes, Mirella Andrade Silva oth de Brito, Adriane Ferreira oth de Carvalho, Flávio Souza oth Sanz, Germán oth Rodrigues, Marcella Ferreira oth da Silva, Artur Christian Garcia oth Thomaz, Douglas Vieira oth de Oliveira, Valéria oth Vaz, Boniek Gontijo oth Lião, Luciano Morais oth Valadares, Marize Campos oth Gil, Eric de Souza oth Costa, Elson Alves oth Noël, François oth Menegatti, Ricardo oth Enthalten in Elsevier Choi, Seung Hee ELSEVIER Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer 2021 an international journal Amsterdam (DE-627)ELV006146201 volume:417 year:2022 day:24 month:01 pages:0 https://doi.org/10.1016/j.bbr.2021.113582 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 35.70 Biochemie: Allgemeines VZ 42.12 Biophysik VZ AR 417 2022 24 0124 0 |
| spelling |
10.1016/j.bbr.2021.113582 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001570.pica (DE-627)ELV055761542 (ELSEVIER)S0166-4328(21)00470-8 DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 35.70 bkl 42.12 bkl Moreira, Lorrane Kelle da Silva verfasserin aut Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. Piperazine ring Elsevier 5-HT1A Elsevier Depression Elsevier Anxiety Elsevier Central nervous system disorders Elsevier Silva, Rafaela Ribeiro oth da Silva, Dayane Moreira oth Mendes, Mirella Andrade Silva oth de Brito, Adriane Ferreira oth de Carvalho, Flávio Souza oth Sanz, Germán oth Rodrigues, Marcella Ferreira oth da Silva, Artur Christian Garcia oth Thomaz, Douglas Vieira oth de Oliveira, Valéria oth Vaz, Boniek Gontijo oth Lião, Luciano Morais oth Valadares, Marize Campos oth Gil, Eric de Souza oth Costa, Elson Alves oth Noël, François oth Menegatti, Ricardo oth Enthalten in Elsevier Choi, Seung Hee ELSEVIER Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer 2021 an international journal Amsterdam (DE-627)ELV006146201 volume:417 year:2022 day:24 month:01 pages:0 https://doi.org/10.1016/j.bbr.2021.113582 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 35.70 Biochemie: Allgemeines VZ 42.12 Biophysik VZ AR 417 2022 24 0124 0 |
| allfields_unstemmed |
10.1016/j.bbr.2021.113582 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001570.pica (DE-627)ELV055761542 (ELSEVIER)S0166-4328(21)00470-8 DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 35.70 bkl 42.12 bkl Moreira, Lorrane Kelle da Silva verfasserin aut Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. Piperazine ring Elsevier 5-HT1A Elsevier Depression Elsevier Anxiety Elsevier Central nervous system disorders Elsevier Silva, Rafaela Ribeiro oth da Silva, Dayane Moreira oth Mendes, Mirella Andrade Silva oth de Brito, Adriane Ferreira oth de Carvalho, Flávio Souza oth Sanz, Germán oth Rodrigues, Marcella Ferreira oth da Silva, Artur Christian Garcia oth Thomaz, Douglas Vieira oth de Oliveira, Valéria oth Vaz, Boniek Gontijo oth Lião, Luciano Morais oth Valadares, Marize Campos oth Gil, Eric de Souza oth Costa, Elson Alves oth Noël, François oth Menegatti, Ricardo oth Enthalten in Elsevier Choi, Seung Hee ELSEVIER Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer 2021 an international journal Amsterdam (DE-627)ELV006146201 volume:417 year:2022 day:24 month:01 pages:0 https://doi.org/10.1016/j.bbr.2021.113582 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 35.70 Biochemie: Allgemeines VZ 42.12 Biophysik VZ AR 417 2022 24 0124 0 |
| allfieldsGer |
10.1016/j.bbr.2021.113582 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001570.pica (DE-627)ELV055761542 (ELSEVIER)S0166-4328(21)00470-8 DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 35.70 bkl 42.12 bkl Moreira, Lorrane Kelle da Silva verfasserin aut Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. Piperazine ring Elsevier 5-HT1A Elsevier Depression Elsevier Anxiety Elsevier Central nervous system disorders Elsevier Silva, Rafaela Ribeiro oth da Silva, Dayane Moreira oth Mendes, Mirella Andrade Silva oth de Brito, Adriane Ferreira oth de Carvalho, Flávio Souza oth Sanz, Germán oth Rodrigues, Marcella Ferreira oth da Silva, Artur Christian Garcia oth Thomaz, Douglas Vieira oth de Oliveira, Valéria oth Vaz, Boniek Gontijo oth Lião, Luciano Morais oth Valadares, Marize Campos oth Gil, Eric de Souza oth Costa, Elson Alves oth Noël, François oth Menegatti, Ricardo oth Enthalten in Elsevier Choi, Seung Hee ELSEVIER Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer 2021 an international journal Amsterdam (DE-627)ELV006146201 volume:417 year:2022 day:24 month:01 pages:0 https://doi.org/10.1016/j.bbr.2021.113582 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 35.70 Biochemie: Allgemeines VZ 42.12 Biophysik VZ AR 417 2022 24 0124 0 |
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In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. Piperazine ring Elsevier 5-HT1A Elsevier Depression Elsevier Anxiety Elsevier Central nervous system disorders Elsevier Silva, Rafaela Ribeiro oth da Silva, Dayane Moreira oth Mendes, Mirella Andrade Silva oth de Brito, Adriane Ferreira oth de Carvalho, Flávio Souza oth Sanz, Germán oth Rodrigues, Marcella Ferreira oth da Silva, Artur Christian Garcia oth Thomaz, Douglas Vieira oth de Oliveira, Valéria oth Vaz, Boniek Gontijo oth Lião, Luciano Morais oth Valadares, Marize Campos oth Gil, Eric de Souza oth Costa, Elson Alves oth Noël, François oth Menegatti, Ricardo oth Enthalten in Elsevier Choi, Seung Hee ELSEVIER Combined use of cisplatin plus natural killer cells overcomes immunoresistance of cisplatin resistant ovarian cancer 2021 an international journal Amsterdam (DE-627)ELV006146201 volume:417 year:2022 day:24 month:01 pages:0 https://doi.org/10.1016/j.bbr.2021.113582 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 35.70 Biochemie: Allgemeines VZ 42.12 Biophysik VZ AR 417 2022 24 0124 0 |
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anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative lqfm005 and its hydroxylated metabolite in mice |
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Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice |
| abstract |
The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. |
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The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. |
| abstract_unstemmed |
The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (K i around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors. |
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Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice |
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Silva, Rafaela Ribeiro da Silva, Dayane Moreira Mendes, Mirella Andrade Silva de Brito, Adriane Ferreira de Carvalho, Flávio Souza Sanz, Germán Rodrigues, Marcella Ferreira da Silva, Artur Christian Garcia Thomaz, Douglas Vieira de Oliveira, Valéria Vaz, Boniek Gontijo Lião, Luciano Morais Valadares, Marize Campos Gil, Eric de Souza Costa, Elson Alves Noël, François Menegatti, Ricardo |
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Silva, Rafaela Ribeiro da Silva, Dayane Moreira Mendes, Mirella Andrade Silva de Brito, Adriane Ferreira de Carvalho, Flávio Souza Sanz, Germán Rodrigues, Marcella Ferreira da Silva, Artur Christian Garcia Thomaz, Douglas Vieira de Oliveira, Valéria Vaz, Boniek Gontijo Lião, Luciano Morais Valadares, Marize Campos Gil, Eric de Souza Costa, Elson Alves Noël, François Menegatti, Ricardo |
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| doi_str |
10.1016/j.bbr.2021.113582 |
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2024-07-06T18:27:43.806Z |
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