Discovery and Structure–Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists

Barbara Preti; Anna Suchankova; Giuseppe Deganutti; Michele Leuenberger; Kerry Barkan; Iga Manulak; Xianglin Huang; Sabrina Carvalho; Graham Ladds; Martin Lochner

doi:10.1021/acs.jmedchem.2c01414

Discovery and Structure–Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists

Barbara Preti, Anna Suchankova, Giuseppe Deganutti, Michele Leuenberger, Kerry Barkan, Iga Manulak, Xianglin Huang, Sabrina Carvalho, Graham Ladds, Martin Lochner

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Abstract

A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5′-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds’ affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.

Original language	English
Pages (from-to)	14864-14890
Number of pages	27
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	21
Early online date	21 Oct 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01414
Publication status	Published - 10 Nov 2022

Bibliographical note

© 2022 The Authors. Published by American Chemical Society
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 work is properly cited..

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This study was supported by the Swiss National Science Foundation (B.P., M.Le. and M.Lo.), the Cambridge Trust (A.S.), the Leverhulme Trust (K.B. and G.L.), an AstraZeneca studentship (S.C.), a British Pharmacological Society Vacation Studentship (I.M.), a China Scholarship Council Cambridge International Scholarship (X.H.), and the BBSRC (G.L.). We thank Matt Ladds for his help with proof checking the statistical analysis and the Analytical Services from the Department of Chemistry, Biochemistry, and Pharmaceutical Sciences, University of Bern, Switzerland, for measuring NMR and MS spectra of synthetic intermediates and final compounds

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title = "Discovery and Structure–Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists",

abstract = "A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5′-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds{\textquoteright} affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.",

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AU - Preti, Barbara

AU - Suchankova, Anna

AU - Deganutti, Giuseppe

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AU - Barkan, Kerry

AU - Manulak, Iga

AU - Huang, Xianglin

AU - Carvalho, Sabrina

AU - Ladds, Graham

AU - Lochner, Martin

N1 - © 2022 The Authors. Published by American Chemical Society 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 work is properly cited..

PY - 2022/11/10

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N2 - A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5′-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds’ affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.

AB - A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5′-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds’ affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.

UR - https://doi.org/10.1021/acs.jmedchem.2c01414

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DO - 10.1021/acs.jmedchem.2c01414

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VL - 65

SP - 14864

EP - 14890

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

Discovery and Structure–Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists

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