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Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Seroto...

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Autores principales: Partyka, Anna, Zagórska, Agnieszka, Kotańska, Magdalena, Walczak, Maria, Jastrzębska-Więsek, Magdalena, Knutelska, Joanna, Bednarski, Marek, Głuch-Lutwin, Monika, Mordyl, Barbara, Janiszewska, Paulina, Wesołowska, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413516/
https://www.ncbi.nlm.nih.gov/pubmed/32764777
http://dx.doi.org/10.1371/journal.pone.0237196
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author Partyka, Anna
Zagórska, Agnieszka
Kotańska, Magdalena
Walczak, Maria
Jastrzębska-Więsek, Magdalena
Knutelska, Joanna
Bednarski, Marek
Głuch-Lutwin, Monika
Mordyl, Barbara
Janiszewska, Paulina
Wesołowska, Anna
author_facet Partyka, Anna
Zagórska, Agnieszka
Kotańska, Magdalena
Walczak, Maria
Jastrzębska-Więsek, Magdalena
Knutelska, Joanna
Bednarski, Marek
Głuch-Lutwin, Monika
Mordyl, Barbara
Janiszewska, Paulina
Wesołowska, Anna
author_sort Partyka, Anna
collection PubMed
description Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT(1A) receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT(1A) receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT(1A) receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α(1)-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.
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spelling pubmed-74135162020-08-13 Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists Partyka, Anna Zagórska, Agnieszka Kotańska, Magdalena Walczak, Maria Jastrzębska-Więsek, Magdalena Knutelska, Joanna Bednarski, Marek Głuch-Lutwin, Monika Mordyl, Barbara Janiszewska, Paulina Wesołowska, Anna PLoS One Research Article Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT(1A) receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT(1A) receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT(1A) receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α(1)-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action. Public Library of Science 2020-08-07 /pmc/articles/PMC7413516/ /pubmed/32764777 http://dx.doi.org/10.1371/journal.pone.0237196 Text en © 2020 Partyka et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Partyka, Anna
Zagórska, Agnieszka
Kotańska, Magdalena
Walczak, Maria
Jastrzębska-Więsek, Magdalena
Knutelska, Joanna
Bednarski, Marek
Głuch-Lutwin, Monika
Mordyl, Barbara
Janiszewska, Paulina
Wesołowska, Anna
Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title_full Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title_fullStr Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title_full_unstemmed Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title_short Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT(1A) receptor partial agonists
title_sort antidepressant-like activity and safety profile evaluation of 1h-imidazo[2,1-f]purine-2,4(3h,8h)-dione derivatives as 5-ht(1a) receptor partial agonists
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413516/
https://www.ncbi.nlm.nih.gov/pubmed/32764777
http://dx.doi.org/10.1371/journal.pone.0237196
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