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 (Ra) adenosine receptors of human platelets and inhibitory (Ri) 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 mumol/l. 5'-N-Methylcarboxamidoadenosine (MECA; IC50 0.81 mumol/l) and 5'-N-carboxamidoadenosine (NCA; IC50 2.1 mumol/l) were less potent, whereas adenosine, 2-chloroadenosine and (-)N6-phenylisopropyladenosine [(-)PIA] exhibit IC50-values of about 1.5 mumol/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 Ri 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 Ri receptors as indicated by a 2,900-fold lower IC50 for the antilipolytic than for the anti-aggregatory effect.(ABSTRACT TRUNCATED AT 250 WORDS)