N-6,5 '-disubstituted adenosine derivatives as partial agonists for the human adenosine A(3) receptor

5'-(Alkylthio)-substituted analogues of N-6-benzyl- and N-6-(3-iodobenzyl)adenosine were synthesized in 37-61% overall yields. The affinities of these compounds for the adenosine A(1), A(2A), and A(3) receptors were determined using rat brain cortex, rat brain striata, and stably transfected hu...

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Published inJournal of medicinal chemistry Vol. 42; no. 8; pp. 1393 - 1400
Main Authors van Tilburg, EW, Kunzel, JVD, de Groote, M, Vollinga, RC, Lorenzen, A, IJzerman, AP
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 22.04.1999
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
SELECTIVE LIGANDS
A RECEPTOR
ANALOGS
AFFINITY
N-6-BENZYLADENOSINE-5'-URONAMIDES
THEOPHYLLINE-7-RIBOSIDE
BRAIN MEMBRANES
RAT-BRAIN
BINDING
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Summary:5'-(Alkylthio)-substituted analogues of N-6-benzyl- and N-6-(3-iodobenzyl)adenosine were synthesized in 37-61% overall yields. The affinities of these compounds for the adenosine A(1), A(2A), and A(3) receptors were determined using rat brain cortex, rat brain striata, and stably transfected human A(3) receptors in HEK 293 cells, respectively. The compounds proved to be selective for the adenosine A(3) receptor and displayed affinities in the nanomolar range. Compounds 8, 10, and 11 had the highest affinities for the A(3) receptor with K-i values ranging from 8.8 to 27.7 nM. In the N-6-benzyl series, compound 4 (LUF 5403), with a 5'-methylthio group, maintained a reasonable affinity and had the highest selectivity for the A(3) receptor. Compound 12 (LUF 5411), with an N-6-(3-iodobenzyl) group and a 5'-(n-propylthio) substituent, had the highest A(3) selectivity of all of the compounds and also displayed high affinity for this receptor (K-i = 44.3 nM). The compounds were also evaluated for their ability to stimulate [S-35]GTP gamma[S] binding in cell membranes expressing the human adenosine A(3) receptor. It appeared that the N-6,5'-disubstituted adenosine derivatives behaved as partial agonists. Compounds 2, 4, 8, and 10 had the highest intrinsic activities. Additionally, when tested in a cAMP assay, these compounds also behaved as partial agonists.
ISSN:0022-2623
DOI:10.1021/jm981090+