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Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold

[Image: see text] Here we describe the design and synthesis of pyrazolo[3,4-d]pyridazines as adenosine receptor (AR) ligands. We demonstrate that the introduction of a 3-phenyl group, together with a 7-benzylamino and 1-methyl group at the pyrazolopyridazine scaffold, generated the antagonist compou...

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Autores principales: Suchankova, Anna, Stampelou, Margarita, Koutsouki, Klontiana, Pousias, Athanasios, Dhingra, Lakshiv, Barkan, Kerry, Pouli, Nicole, Marakos, Panagiotis, Tenta, Roxane, Kolocouris, Antonios, Lougiakis, Nikolaos, Ladds, Graham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9190043/
https://www.ncbi.nlm.nih.gov/pubmed/35707146
http://dx.doi.org/10.1021/acsmedchemlett.2c00052
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author Suchankova, Anna
Stampelou, Margarita
Koutsouki, Klontiana
Pousias, Athanasios
Dhingra, Lakshiv
Barkan, Kerry
Pouli, Nicole
Marakos, Panagiotis
Tenta, Roxane
Kolocouris, Antonios
Lougiakis, Nikolaos
Ladds, Graham
author_facet Suchankova, Anna
Stampelou, Margarita
Koutsouki, Klontiana
Pousias, Athanasios
Dhingra, Lakshiv
Barkan, Kerry
Pouli, Nicole
Marakos, Panagiotis
Tenta, Roxane
Kolocouris, Antonios
Lougiakis, Nikolaos
Ladds, Graham
author_sort Suchankova, Anna
collection PubMed
description [Image: see text] Here we describe the design and synthesis of pyrazolo[3,4-d]pyridazines as adenosine receptor (AR) ligands. We demonstrate that the introduction of a 3-phenyl group, together with a 7-benzylamino and 1-methyl group at the pyrazolopyridazine scaffold, generated the antagonist compound 10b, which displayed 21 nM affinity and a residence time of ∼60 min, for the human A(1)R, 55 nM affinity and a residence time of ∼73 min, for the human A(3)R and 1.7 μΜ affinity for the human A(2B)R while not being toxic. Strikingly, the 2-methyl analog of 10b, 15b, had no significant affinity. Docking calculations and molecular dynamics simulations of the ligands inside the orthosteric binding area suggested that the 2-methyl group in 15b hinders the formation of hydrogen bonding interactions with N(6.55) which are considered critical for the stabilization inside the orthosteric binding cavity. We, therefore, demonstrate that 10a is a novel scaffold for the development of high affinity AR ligands. From the mutagenesis experiments the biggest effect was observed for the Y271(7.46)A mutation which caused an ∼10-fold reduction in the binding affinity of 10b.
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spelling pubmed-91900432022-06-14 Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold Suchankova, Anna Stampelou, Margarita Koutsouki, Klontiana Pousias, Athanasios Dhingra, Lakshiv Barkan, Kerry Pouli, Nicole Marakos, Panagiotis Tenta, Roxane Kolocouris, Antonios Lougiakis, Nikolaos Ladds, Graham ACS Med Chem Lett [Image: see text] Here we describe the design and synthesis of pyrazolo[3,4-d]pyridazines as adenosine receptor (AR) ligands. We demonstrate that the introduction of a 3-phenyl group, together with a 7-benzylamino and 1-methyl group at the pyrazolopyridazine scaffold, generated the antagonist compound 10b, which displayed 21 nM affinity and a residence time of ∼60 min, for the human A(1)R, 55 nM affinity and a residence time of ∼73 min, for the human A(3)R and 1.7 μΜ affinity for the human A(2B)R while not being toxic. Strikingly, the 2-methyl analog of 10b, 15b, had no significant affinity. Docking calculations and molecular dynamics simulations of the ligands inside the orthosteric binding area suggested that the 2-methyl group in 15b hinders the formation of hydrogen bonding interactions with N(6.55) which are considered critical for the stabilization inside the orthosteric binding cavity. We, therefore, demonstrate that 10a is a novel scaffold for the development of high affinity AR ligands. From the mutagenesis experiments the biggest effect was observed for the Y271(7.46)A mutation which caused an ∼10-fold reduction in the binding affinity of 10b. American Chemical Society 2022-05-31 /pmc/articles/PMC9190043/ /pubmed/35707146 http://dx.doi.org/10.1021/acsmedchemlett.2c00052 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Suchankova, Anna
Stampelou, Margarita
Koutsouki, Klontiana
Pousias, Athanasios
Dhingra, Lakshiv
Barkan, Kerry
Pouli, Nicole
Marakos, Panagiotis
Tenta, Roxane
Kolocouris, Antonios
Lougiakis, Nikolaos
Ladds, Graham
Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title_full Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title_fullStr Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title_full_unstemmed Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title_short Discovery of a High Affinity Adenosine A(1)/A(3) Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold
title_sort discovery of a high affinity adenosine a(1)/a(3) receptor antagonist with a novel 7-amino-pyrazolo[3,4-d]pyridazine scaffold
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9190043/
https://www.ncbi.nlm.nih.gov/pubmed/35707146
http://dx.doi.org/10.1021/acsmedchemlett.2c00052
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