Publication
Title
Dual N⁶/C7-substituted 7-deazapurine and tricyclic ribonucleosides with affinity for G protein-coupled receptors
Author
Abstract
Various purine-based nucleoside analogues have demonstrated unexpected affinity for nonpurinergic G protein-coupled receptors (GPCRs), such as opioid and serotonin receptors. In this work, we synthesized a small library of new 7-deazaadenosine and pyrazolo-[3,4-d]-pyrimidine riboside analogues, featuring dual C7 and N-6 modifications and assessed their affinity for various GPCRs. During the course of the synthesis of 7-ethynyl pyrazolo-[3,4-d]-pyrimidine ribosides, we observed the formation of an unprecedented tricyclic nucleobase, formed via a 6-endo-dig ring closure. The synthesis of this tricyclic nucleoside was optimized, and the substrate scope for such cyclization was further explored because it might avail further exploration in the nucleoside field. From displacement experiments on a panel of GPCRs and transporters, combining C7 and N-6 modifications afforded noncytotoxic nucleosides with micromolar and submicromolar affinity for different GPCRs, such as the 5-hydroxytryptamine (5-HT)(2B), kappa-opioid (KOR), and sigma(1/2) receptor. These results corroborate that the novel nucleoside analogues reported here are potentially useful starting points for the further development of modulators of GPCRs and transmembrane proteins.
Language
English
Source (journal)
ACS medicinal chemistry letters. - -
Publication
2023
ISSN
1948-5875
DOI
10.1021/ACSMEDCHEMLETT.3C00427
Volume/pages
15 :1 (2023) , p. 81-86
ISI
001141726400001
Pubmed ID
38229744
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 01.02.2024
Last edited 08.02.2024
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