Inhibition of human mast cell activation with the novel selective adenosine A2B receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)
Inhibition of human mast cell activation with the novel selective adenosine A2B receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)
复制标题
DOI：
10.1016/s0006-2952(01)00765-1
复制
发表时间：
2001-11-01
影响因子：
5.8
通讯作者：
Biaggioni, I
中科院分区：
文献类型：
--
作者：
Feoktistov, I;Garland, EM;Biaggioni, I
抗哮喘药物恩普罗茶碱是第一个已知的选择性，但不是有效的，A（2B）拮抗剂。基于黄嘌呤类化合物的构效关系（SAR），我们设计了一种新的选择性腺苷A（2B）受体拮抗剂3-异丁基-8-吡咯烷黄嘌呤（IPDX），其活性高于恩普罗茶碱。IPDX置换[H-3] ZM 241385（[H-3]4-（2-[7-氨基-2-（2-呋喃基）[1，2，4]三唑并[2，3-a]-[1，3，5]三嗪-5-基氨基]乙基）苯酚），Ki值为470 +/- 2 nM，并抑制人红白血病（HEL）细胞中A（2B）依赖性环AMP（cAMP）积累，Ki值为470 +/-2 nM。B值为625 +/- 71 nM。我们发现，IPDX对人A（2B）受体的选择性高于恩普罗茶碱。对人A（2B）腺苷受体的选择性分别比对人A（1）（Ki值为24 +/- 8 μ M）、人A（2A）（Ki值为36 +/- 8 μ M）和人A（3）（Ki值为53 +/- 10 μ M）腺苷受体的选择性高38、55和82倍。IPDX抑制人肥大细胞（HMC-1）中NECA（5 '-N-乙基羧酰胺腺苷）诱导的白细胞介素-8分泌，其效力接近于HEL细胞中A（2B）介导的cAMP积累，从而证实了A（2B）腺苷受体在介导人肥大细胞活化中的作用。由于腺苷通过人肥大细胞活化触发哮喘患者的支气管收缩，IPDX可能成为开发新的抗哮喘药物的基础，与恩丙茶碱相比，其性质有所改善。我们的数据表明，IPDX可用作区分A（2B）和其他腺苷受体介导的反应的工具。(C)2001 Elsevier Science Inc. All rights reserved.
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 [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]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 AM), human A(2A) (K-B value of 36 +/- 8 AM), and human A(3) (K-i value of 53 +/- 10 muM) 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. (C) 2001 Elsevier Science Inc. All rights reserved.