4.5 Article

N-terminal domains in mouse and human 5-hydroxytryptamine3A receptors confer partial agonist and antagonist properties to benzylidene analogs of anabaseine

期刊

出版社

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.101485

关键词

-

资金

  1. NINDS NIH HHS [NS 43438] Funding Source: Medline

向作者/读者索取更多资源

The present study tested the hypothesis that mouse and human 5-hydroxytryptamine(3A) (5-HT3A) receptors may be differentially modulated by benzylidene analogs of anabaseine ( BA) and that these analogs may be useful in assessing residues involved in receptor gating. Mouse and human wild-type and mouse and human chimeric 5-HT3A receptors expressed in Xenopus oocytes were evaluated with the two-electrode voltage clamp technique. Our previous studies demonstrated that 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) is an antagonist at the mouse wild-type 5-HT3A receptor, but that its metabolites 3-(2-hydroxy, 4-methoxybenzylidene)-anabaseine (2-OHMBA), 3-(2-methoxy, 4-hydroxybenzylidene)-anabaseine (4-OHMBA), and 3-(2,4-dihydroxybenzylidene)-anabaseine (2,4-DiOHBA) are partial agonists (J Pharmacol Exp Ther, 299: 1112-1117, 2001). In the human wild- type (HWT) 5-HT3A receptor, none of the BA compounds possessed partial agonist activity. BA compounds antagonized 1.5 mu M 5-HT-mediated (EC50) responses in the HWT 5-HT3A receptor with a rank order of potency (IC50 in mu M) of 2-OHMBA (1.5 +/- 0.1) > DMXBA (3.1 +/- 0.2) > 4-OHMBA (7.4 +/- 0.5) > 2,4-DiOHBA (12.8 +/- 0.7). In mouse receptor chimeras containing N-terminal human receptor orthologs, 2-OHMBA inhibited 5-HT-mediated (EC50) currents with IC50 values of 2.0 +/- 0.08 and 3.0 +/- 0.13 mu M, respectively. In human receptor chimeras containing N- terminal mouse receptor orthologs, 2-OHMBA displayed partial agonist activities with EC50 values of 1.3 +/- 0.15 and 5.0 +/- 0.4 mu M; efficacies were 43 and 57%, respectively. Thus, amino acids present in the distal one-third of the N terminus of mouse and human 5-HT3A receptors are necessary and sufficient to confer partial agonist or antagonist properties of 2-OHMBA.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据