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Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.


ABSTRACT: Antagonism of the human adenosine A3 receptor (hA3R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA3R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA3R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA3R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA3R antagonist.

SUBMITTER: Huang X 

PROVIDER: S-EPMC11320584 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.

Huang Xianglin X   Chorianopoulou Anna A   Kalkounou Panagoula P   Georgiou Maria M   Pousias Athanasios A   Davies Amy A   Pearce Abigail A   Harris Matthew M   Lambrinidis George G   Marakos Panagiotis P   Pouli Nicole N   Kolocouris Antonios A   Lougiakis Nikolaos N   Ladds Graham G  

Journal of medicinal chemistry 20240729 15


Antagonism of the human adenosine A<sub>3</sub> receptor (hA<sub>3</sub>R) has potential therapeutic application. Alchemical relative binding free energy calculations of <b>K18</b> and <b>K32</b> suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA<sub>3</sub>R affinity. Of the 25 new analogues synthesized, <b>37</b> and <b>74</b> showed improved hA<sub>3</sub>R affinity compared to <b>K18  ...[more]

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