Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed
Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed
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DOI：
10.1111/j.1476-5381.1995.tb15071.x
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发表时间：
1995-10
影响因子：
7.3
通讯作者：
R. Leurs;M. Tulp;W. Menge;M. Adolfs;O. Zuiderveld;H. Timmerman
中科院分区：
文献类型：
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作者：
R. Leurs;M. Tulp;W. Menge;M. Adolfs;O. Zuiderveld;H. Timmerman
1 在本研究中，我们评估了强效组胺 H3 受体拮抗剂 iodophenpropit (IPP) 与原型拮抗剂 thioperamide 的受体选择性。 2 IPP 被证明是一种有效的竞争性 H3 受体拮抗剂，针对 (R)-α-甲基组胺诱导的豚鼠空肠电诱发收缩抑制进行测量（pA2=9.12±0.06，Schild 斜率：1.0±0.1，n=8）。在同一测定中，硫过酰胺的效力稍差（pA2 = 8.9±0.2）。 3 在放射性配体结合研究中，IPP 显示出对 H3 受体的高亲和力。未标记的 IPP 取代与大鼠皮质膜结合的 [125I]-IPP 导致 Ki 值为 0.97 ± 0.06 nM (n = 3)。相反，IPP 对组胺 H1 和 H2 受体仅表现出弱亲和力。 IPP 取代分别与豚鼠 H1 和人 H2 受体结合的 [3H]-美吡拉明和 [125I]-碘氨基波替丁，导致 Ki 值为 1.71±0.32 μm (n=3) 和 2.28±0.81 μm (n=3)。对于硫哌丁胺，对 H1、H2 和 H3 受体的亲和力分别为 >10 μm、>10 μm 和 4.3±1.6 nM (n=7)。 4 在 39 种不同的受体结合测定中测试 IPP 和硫过酰胺显示，IPP 对 5-羟色胺 5-HT3 受体 (Ki=11± nM，n=3)、α2-肾上腺素受体 (Ki=120±5 nM，n=3) 和 sigma 受体 (Ki=170±70 nM，n=3) 显示出相对较高的亲和力。硫哌丁胺对 5-HT3 受体（Ki=120±30 nM，n=3）和 sigma 受体（Ki=180±90 nM，n=3）表现出相对较高的亲和力。 5 由于大脑中组胺 H3 受体的密度较低，IPP 与 5-HT3-、α2- 和 sima 受体的相互作用可能会干扰 [125I]-IPP 与大鼠皮质膜的结合。然而，在该制剂中，[125I]-IPP 结合不受昂丹司琼、育亨宾或氟哌啶醇的影响。 6 与 5-HT3 受体的相互作用不仅限于 IPP 或硫哌丁胺，还发现与其他 H3 受体拮抗剂的相互作用。有效的 H3 受体激动剂 Imetit（一种属于 IPP 同一化学类别的化合物）也与 5-HT3 受体相互作用 (Ki=240±40 nM)。相反，组胺或 H3 受体激动剂 (R)-α-甲基组胺对 5-HT3 受体没有亲和力。 7 在豚鼠离体回肠中，imetit 引起浓度依赖性收缩，导致 pD2 值为 4.72±0.03 (n = 9)。昂丹司琼拮抗收缩，产生 7.1±0.1 (n=9) 的 pA2 值。同样，昂丹司琼拮抗 5-HT3 受体激动剂 2-甲基-5-HT 引起的收缩，pA2 值为 7.3±0.1 (n=4)。 IPP 和硫过酰胺并不模拟 2-甲基-5-HT，而是非竞争性抑制该制剂的 2-甲基-5-HT 诱导的收缩。 8 在 5-HT3 活性体内模型中，Von Bezold Jarisch 反射，硫哌丁胺在低剂量下表现出拮抗作用，这与 5-HT3 受体位点的亲和力密切相关。然而，在较高剂量下，没有观察到进一步的 5-HT3 受体拮抗作用。对于 IPP，体内未观察到 5-HT3 受体活性。 9 在本研究中，我们表明许多被认为具有高选择性的 H3 受体化合物（包括原型药物硫哌丁胺）也与 5-HT3 受体相互作用，尽管药物浓度较高。
1 In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2 IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)‐α‐methylhistamine‐induced inhibition of electrically‐evoked contractions of the guinea‐pig jejunum (pA2=9.12±0.06, Schild slope: 1.0±0.1, n=8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9±0.2). 3 In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]‐IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 ± 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1‐ and H2 receptor. Displacement of [3H]‐mepyramine and [125I]‐iodoaminopotentidine binding to respectively guinea‐pig H1‐ and human H2 receptors by IPP resulted in Ki values of 1.71±0.32 μm (n=3) and 2.28±0.81 μm (n=3). For thioperamide the affinities for the H1‐, H2‐ and H3 receptor were respectively >10 μm, >10 μm and 4.3±1.6 nM (n=7). 4 Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5‐hydroxytryptamine 5‐HT3 receptor (Ki=11± nM, n=3), the α2‐adrenoceptor (Ki=120±5 nM, n=3) and the sigma receptor (Ki=170±70 nM, n=3). Thioperamide showed relatively high affinity for the 5‐HT3 receptor (Ki=120±30 nM, n=3) and the sigma receptor (Ki=180±90 nM, n=3). 5 Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5‐HT3‐, the α2‐ and the sima receptor might interfere with [125I]‐IPP binding to rat cortex membranes. Yet, in this preparation [125I]‐IPP binding was not influenced by ondansetron, yohimbine or haloperidol. 6 The interaction with the 5‐HT3 receptor was not restricted to IPP or thioperamide, but was also found with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belonging to the same chemical class of IPP, also interacted with the 5‐HT3 receptor (Ki=240±40 nM). In contrast, histamine or the H3 receptor agonist, (R)‐α‐methylhistamine showed no affinity for the 5‐HT3 receptor. 7 In the guinea‐pig isolated ileum, imetit evoked concentration‐dependent contractions, resulting in a pD2 value of 4.72±0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 value of 7.1±0.1 (n=9). Similarly ondansetron antagonized the contractions evoked by the 5‐HT3 receptor agonist, 2‐methyl‐5‐HT with a pA2 value of 7.3±0.1 (n=4). IPP and thioperamide did not mimic 2‐methyl‐5‐HT but non‐competitively inhibited the 2‐methyl‐5‐HT‐induced contractions of this preparation. 8 In an in vivo model for 5‐HT3 activity, the Von Bezold Jarisch reflex, thioperamide showed antagonism in low dosages, which correlated well with the affinity for the 5‐HT3 receptor site. Yet, at higher dosages no further 5‐HT3 receptor antagonism was observed. For IPP no 5‐HT3 receptor activity could be observed in vivo. 9 In the present study we showed that many H3 receptor compounds, that are regarded as highly selective (including the prototype drug, thioperamide), also interact with the 5‐HT3 receptor, albeit at higher drug concentrations.