Inhibition of human mast cell activation with the novel selective adenosine A 2B receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)

Abstract

The antiasthmatic drug enprofylline was the first known selective, though not potent, A 2B antagonist. On the basis of structure-activity relationships (SARs) of xanthine derivatives, we designed a novel selective adenosine A 2B receptor antagonist, 3-isobutyl-8-pyrrolidinoxanthine (IPDX), with potency greater than that of enprofylline. IPDX displaced [ 3H]ZM241385 ([ 3H]4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3- a]-[1,3,5]triazin-5-ylamino]ethyl)phenol) from human A 2B adenosine receptors with a K i value of 470 ± 2 nM and inhibited A 2B-dependent cyclic AMP (cAMP) accumulation in human erythroleukemia (HEL) cells with a K B value of 625 ± 71 nM. We found that IPDX was more selective than enprofylline toward human A 2B receptors. It was 38-, 55-, and 82-fold more selective for human A 2B than for human A 1 ( K i value of 24 ± 8 μM), human A 2A ( K B value of 36 ± 8 μM), and human A 3 ( K i value of 53 ± 10 μM) adenosine receptors, respectively. IPDX inhibited NECA (5′- N-ethylcarboxamidoadenosine)-induced interleukin-8 secretion in human mast cells (HMC-1) with a potency close to that determined for A 2B-mediated cAMP accumulation in HEL cells, thus confirming the role of A 2B adenosine receptors in mediating human mast cell activation. Since adenosine triggers bronchoconstriction in asthmatic patients through human mast cell activation, IPDX may become a basis for the development of new antiasthmatic drugs with improved properties compared with those of enprofylline. Our data demonstrate that IPDX can be used as a tool to differentiate between A 2B and other adenosine receptor-mediated responses.