Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes
Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes
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DOI：
10.1124/mol.107.035410
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发表时间：
2007-09-01
影响因子：
3.6
通讯作者：
Malysz, John
中科院分区：
文献类型：
--
作者：
Gronlien, Jens Halvard;Hakerud, Monika;Malysz, John
α 7烟碱乙酰胆碱受体（nAChR）的选择性调节被认为调节精神分裂症、阿尔茨海默病和其他痴呆中受损的过程。靶向α 7 nAChR的一种方法是通过正变构调节。结构多样化的化合物，包括PNU 120596、4-萘-1-基-3a，4，5，9 b-四氢-3- H-环戊[ c]喹啉-8-磺酸酰胺（TQS）和5-羟基吲哚（5- HI）已被确定为正变构调节剂（PAMS），但其受体相互作用和药理学特征仍有待充分阐明。在这项研究中，我们研究了这些化合物在人类7 nAChRs，表达在非洲爪蟾卵母细胞，沿着与染料木素，酪氨酸激酶抑制剂的相互作用。发现染料木黄酮作为PAM起作用。观察到两种类型的PAM配置文件。5-HI和染料木素主要影响表观峰值电流（I型），而PNU- 120596和TQS增加表观峰值电流，并诱发明显的弱衰减电流（II型）。对激动剂[ ACh，3-[（3E）-3-[（2，4-二甲氧基苯基）亚甲基]-5，6-二氢-4H-吡啶-2-基]吡啶二盐酸盐（GTS- 21）和N-[（3R）-1-氮杂双环[ 2.2.2]辛-3基]-4-氯苯甲酰胺盐酸盐（PNU- 282987）]的作用，尽管II型PAM的作用更大。当α 7 nAChRs脱敏后应用时，II型而不是I型PAM可以重新激活α 7电流。两种类型的PAM也增加ACh诱发的α 7窗口电流，II型PAM通常显示更大的增强作用。在表达人α 4 β 2或α 3 β 4 nAChR的人胚肾293细胞中，测试的PAM均未增加尼古丁诱发的Ca 2+瞬变，尽管5- HI、染料木素和TQS观察到一些抑制作用。总之，我们的研究揭示了两种不同的α 7 PAM谱，这可以为体内调节α 7 nAChR和开发用于中枢神经系统适应症的新疗法提供独特的机会。
Selective modulation of alpha 7 nicotinic acetylcholine receptors ( nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target alpha 7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU120596, 4- naphthalene- 1- yl- 3a, 4,5,9b- tetrahydro- 3- H- cyclopenta[ c] quinoline- 8- sulfonic acid amide ( TQS), and 5- hydroxyindole ( 5- HI) have been identified as positive allosteric modulators ( PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. In this study, we investigated interactions of these compounds at human 7 nAChRs, expressed in Xenopus laevis oocytes, along with genistein, a tyrosine kinase inhibitor. Genistein was found to function as a PAM. Two types of PAM profiles were observed. 5- HI and genistein predominantly affected the apparent peak current ( type I) whereas PNU- 120596 and TQS increased the apparent peak current and evoked a distinct weakly decaying current ( type II). Concentrationresponses to agonists [ ACh, 3-[( 3E)- 3-[( 2,4- dimethoxyphenyl) methylidene]- 5,6- dihydro- 4H- pyridin- 2- yl] pyridine dihydrochloride ( GTS- 21), and N-[( 3R)- 1- azabicyclo[ 2.2.2] oct- 3yl]- 4- chlorobenzamide hydrochloride ( PNU- 282987)] were potentiated by both types, although type II PAMs had greater effects. When applied after alpha 7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate alpha 7 currents. Both types of PAMs also increased the ACh- evoked alpha 7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotineevoked Ca2+ transients in human embryonic kidney 293 cells expressing human alpha 4 beta 2 or alpha 3 beta 4 nAChRs, although some inhibition was noted for 5- HI, genistein, and TQS. In summary, our studies reveal two distinct alpha 7 PAM profiles, which could offer unique opportunities for modulating alpha 7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.