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)a denosine were synthesized in 37-61% overall yields. The affinities of these compounds for the adenosine A(1), A(2A), and A(3) receptors were determine d using rat brain cortex, rat brain striata, and stably transfected human A (3) receptors in HEK 293 cells, respectively. The compounds proved to be se lective for the adenosine A(3) receptor and displayed affinities in the nan omolar 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 rea sonable affinity and had the highest selectivity for the A(3) receptor. Com pound 12 (LUF 5411), with an N-6-(3-iodobenzyl) group and a 5'-(n-propylthi o) substituent, had the highest A(3) selectivity of all of the compounds an d also displayed high affinity for this receptor (K-i = 44.3 nM). The compo unds 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 par tial agonists. Compounds 2, 4, 8, and 10 had the highest intrinsic activiti es. Additionally, when tested in a cAMP assay, these compounds also behaved as partial agonists.