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Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold
We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABA(A)) subtype receptor. Continuing the study in this field, we report here th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470557/ https://www.ncbi.nlm.nih.gov/pubmed/30901916 http://dx.doi.org/10.3390/ijms20061438 |
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author | Guerrini, Gabriella Vergelli, Claudia Cantini, Niccolò Giovannoni, Maria Paola Daniele, Simona Mascia, Maria Paola Martini, Claudia Crocetti, Letizia |
author_facet | Guerrini, Gabriella Vergelli, Claudia Cantini, Niccolò Giovannoni, Maria Paola Daniele, Simona Mascia, Maria Paola Martini, Claudia Crocetti, Letizia |
author_sort | Guerrini, Gabriella |
collection | PubMed |
description | We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABA(A)) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 μM have been selected for electrophysiological studies on recombinant α1β2γ2L GABA(A) receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABA(A)R in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 μM (+54%), and it enhances the chlorine current at ≥0.01 μM. Finally, compound 6g, acting as a null modulator at α1β2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/β− ‘non-traditional’ benzodiazepine site. |
format | Online Article Text |
id | pubmed-6470557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64705572019-04-26 Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold Guerrini, Gabriella Vergelli, Claudia Cantini, Niccolò Giovannoni, Maria Paola Daniele, Simona Mascia, Maria Paola Martini, Claudia Crocetti, Letizia Int J Mol Sci Article We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABA(A)) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 μM have been selected for electrophysiological studies on recombinant α1β2γ2L GABA(A) receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABA(A)R in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 μM (+54%), and it enhances the chlorine current at ≥0.01 μM. Finally, compound 6g, acting as a null modulator at α1β2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/β− ‘non-traditional’ benzodiazepine site. MDPI 2019-03-21 /pmc/articles/PMC6470557/ /pubmed/30901916 http://dx.doi.org/10.3390/ijms20061438 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Guerrini, Gabriella Vergelli, Claudia Cantini, Niccolò Giovannoni, Maria Paola Daniele, Simona Mascia, Maria Paola Martini, Claudia Crocetti, Letizia Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title | Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title_full | Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title_fullStr | Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title_full_unstemmed | Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title_short | Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold |
title_sort | synthesis of new gaba(a) receptor modulator with pyrazolo[1,5-a]quinazoline (pq) scaffold |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470557/ https://www.ncbi.nlm.nih.gov/pubmed/30901916 http://dx.doi.org/10.3390/ijms20061438 |
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