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

Citation
I. Feoktistov et al., Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX), BIOCH PHARM, 62(9), 2001, pp. 1163-1173
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
9
Year of publication
2001
Pages
1163 - 1173
Database
ISI
SICI code
0006-2952(20011101)62:9<1163:IOHMCA>2.0.ZU;2-M
Abstract
The antiasthmatic drug enprofylline was the first known selective, though n ot potent, A(2B) antagonist. On the basis of structure-activity relationshi ps (SARs) of xanthine derivatives, we designed a novel selective adenosine A(2B) receptor antagonist, 3-isobutyl-8-pyrrolidinoxanthine (IPDX), with po tency greater than that of enprofylline. IPDX displaced [H-3]ZM241385 ([H-3 ]4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a]-[1,3,5]triazin-5-ylamino]e thyl)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 hum an 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 huma n A(1) (K-i value of 24 +/- 8 AM), human A(2A) (K-B value of 36 +/- 8 AM), and human A(3) (K-i value of 53 +/- 10 muM) adenosine receptors, respective ly. IPDX inhibited NECA (5'-N-ethylcarboxamidoadenosine)- induced interleuk in-8 secretion in human mast cells (HMC-1) with a potency close to that det ermined for A(2B)-mediated cAMP accumulation in HEL cells, thus confirming the role of A(2B) adenosine receptors in mediating human mast cell activati on. Since adenosine triggers bronchoconstriction in asthmatic patients thro ugh 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 diff erentiate between A(2B) and other adenosine receptor-mediated responses. (C ) 2001 Elsevier Science Inc. All rights reserved.