Truncated N6-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished binding at the hA2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA2AAR agonists. C2 substitution probed geometrically through hA2AAR-docking, was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA2AAR agonist and hA3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.
Truncated N6-substituted-(N)-methanocarba-adenosine derivatives
with 2-hexynyl substitution
were synthesized to examine parallels with corresponding 4′-thioadenosines.
Hydrophobic N6 and/or C2 substituents were tolerated in
A3AR binding, but only an unsubstituted 6-amino group with
a C2-hexynyl group promoted high hA2AAR affinity. A small
hydrophobic alkyl (4b and 4c) or N6-cycloalkyl group (4d) showed
excellent binding affinity at the hA3AR and was better
than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f–4i did not differ significantly, with Ki values of 7.8–16.0 nM. N6-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects
in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis
model. Most compounds strongly inhibited TGF-β1-induced collagen
I upregulation, and their A3AR binding affinities were
proportional to antifibrotic effects; 4b was most potent
(IC50 = 0.83 μM), indicating its potential as a good
therapeutic candidate for treating renal fibrosis.
The truncated C2- and C8-substituted-4′-thioadenosine derivatives 4a-d were synthesized from D-mannose, using palladium-catalyzed cross coupling reactions as key steps. In this study, an A3 adenosine receptor (AR) antagonist, truncated 4′-thioadenosine derivative 3 was successfully converted into a potent A2AAR agonist 4a (Ki = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N6-substituted. However, C8-substitution greatly reduced binding affinity at the human A2AAR. All synthesized compounds 4a-d maintained their affinity at the human A3AR, but 4a was found to be a competitive A3AR antagonist/A2AAR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted-4′-thioadenosine derivatives 4a and 4b can serve as a novel template for the development of new A2AAR ligands.
The purpose of this study is to explore the family experiences of women with children with adult developmental disabilities to understand what kind of life the individual lives in the family and to know the meaning of the experience. The research method was carried out by Clandinin and Connelly (2000)’s narrative exploration, which is suitable for understanding the experience of the research participants. Participants in this study were 3 women who had children with developmental disabilities aged 21 years or older, and data were collected through in-depth interviews, conversation records, observations, and research diaries of more than 3 times. As a result of exploring the narratives of the research participants, the research participants experienced conflicts with their spouses due to the care imbalance in their relationship with their families after becoming mothers, and had negative experiences of being denied their children with disabilities from their families. I had a positive experience, such as dreaming of a future with my family. From the results of this study, as a result of discussing the personal and social validity of the family experience of women who raised children with developmental disabilities until adulthood, the need for a change in family culture to alleviate the care role concentrated on the mother, targeting all family members Discussed the need for disability acceptance counseling and the need for measures to prevent discrimination and violence within the family.
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