Effects of several 5?-carboxamide derivatives of adenosine on adenosine receptors of human platelets and rat fat cells

Abstract

The effects of several 5′-carboxamide derivatives of adenosine on stimulatory (R_a) adenosine receptors of human platelets and inhibitory (R_i) adenosine receptors of rat fat cells have been compared. 5′-N-Cyclopropylcarboxamidoadenosine (CPCA) and 5′-N-ethylcarboxamidoadenosine (NECA) most potently inhibited ADP-induced aggregation of human platelets as shown by IC₅₀-values of 0.24 and 0.34 μmol/l. 5′-N-Methylcarboxamidoadenosine (MECA; IC₅₀ 0.81 μmol/l) and 5′-N-carboxamidoadenosine (NCA; IC₅₀ 2.1 μmol/l) were less potent, whereas adenosine, 2-chloroadenosine and (-)N⁶-phenylisopropyladenosine [(-)PIA] exhibit IC₅₀-values of about 1.5 μmol/l. Nearly the same rank order of potency was obtained for stimulation of adenylate cyclase activity of platelet membranes and for inhibition of [³H]NECA binding to human platelets. In order to examine the effects of the carboxamide analogues on R_i adenosine receptors of rat fat cells inhibition of lipolysis and adenylate cyclase were studied. (-)PIA was the most potent inhibitor of lipolysis as shown by an IC₅₀ of 0.5 nmol/l, followed by CPCA (IC₅₀ 1.1 nmol/l) and NECA (IC₅₀ 1.3 nmol/l), whereas MECA (IC₅₀ 17.9 nmol/l) and NCA (IC₅₀ 20.1 nmol/l) were much less potent than NECA in inhibiting lipolysis. Similar results were obtained for inhibition of adenylate cyclase activity of fat cell membranes and for competition with [³H]PIA binding to fat cell membranes. The relative potencies of the adenosine analogues at both receptor subclasses were calculated from the ratio of the IC₅₀-values for inhibition of platelet aggregation and of lipolysis. (-)PIA showed the highest selectivity for R _i receptors as indicated by a 2,900-fold lower IC₅₀ for the antilipolytic than for the antiaggregatory effect. The R_a/R_i activity ratio for NECA was about 260, for CPCA 220, for NCA 105 and for MECA 45. These results indicate that all 5′-carboxamide adenosine derivatives are more potent agonists at R_i receptors than at R_a receptors. Since MECA has a higher selectivity for R_a receptors than NECA, it may be useful for the characterization of stimulatory adenosine receptors in different tissues.