2',3'-Dideoxy-N6-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors.
The 2',3'-dideoxy analogue of the potent A1 receptor agonist, N6-cyclohexyladenosine (CHA), was synthesized as a potential antagonist for the A1 adenosine receptor. In studies on adenylate cyclase 2',3'-dideoxy-N6-cyclohexyladenosine (ddCHA) did not show agonist properties at A1 or at A2 receptors. However, it antagonized the inhibition by R-PIA of adenylate cyclase activity of fat cell membranes via A1 receptors with a Ki value of 13 microM. ddCHA competed for the binding of the selective A1 receptor antagonist, [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX), to rat brain membranes with a Ki value of 4.8 microM; GTP did not affect the competition curve. In contrast to the marked stereoselectivity of the A1 receptor for the alpha- and the natural beta-anomer of adenosine, the alpha-anomer of ddCHA showed a comparable affinity for the A1 receptor (K1 value 13.9 microM). These data indicate that the 2'- and 3'-hydroxy groups of adenosine and its derivatives are required for agonist activity at and high affinity binding to A1 adenosine receptors and for the distinction between the alpha- and beta-forms.
Lohse
M J
MJ
Pharmakologisches Institut, Heidelberg, F.R.G.
Klotz
K N
KN
Diekmann
E
E
Friedrich
K
K
Schwabe
U
U
D000262:Adenylyl Cyclases / Q000032:analysis*; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D001921:Brain / Q000201:enzymology; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008566:Membranes / Q000201:enzymology; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects*
D015224:Dideoxynucleosides; D011983:Receptors, Purinergic; C058238:2',3'-dideoxy-N(6)-cyclohexyladenosine; D000262:Adenylyl Cyclases