期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 18, 期 9, 页码 2813-2819出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.04.001
关键词
nucleoside; G protein-coupled receptor; mouse; adenosine receptor; radioligand binding
资金
- Intramural NIH HHS [Z01 DK031117-20] Funding Source: Medline
- NHLBI NIH HHS [R01 HL077707-04, R01 HL077707] Funding Source: Medline
2-Chloro-5'-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0] hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A(3) adenosine receptor ( AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A(1)AR. Therefore, we varied substituents at the N-6 and C2 positions in search of compounds that have improved A(3)AR selectivity and are species independent. An N-6-methyl analogue was balanced in affinity at mouse A(1)/A(3)ARs, with high selectivity in comparison to the A(2A)AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A(3)AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A3AR selectivity more effectively than similar chains attached at the 3-position of the N-6-benzyl group. Published by Elsevier Ltd.
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