α7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues

被引：25

作者：

Briggs, C. A. ^{[1
]}

Schrimpf, M. R. ^{[1
]}

Anderson, D. J. ^{[1
]}

Gubbins, E. J. ^{[1
]}

Gronlien, J. H. ^{[1
]}

Hakerud, M. ^{[1
]}

Ween, H. ^{[1
]}

Thorin-Hagene, K. ^{[1
]}

Malysz, J. ^{[1
]}

Li, J. ^{[1
]}

Bunnelle, W. H. ^{[1
]}

Gopalakrishnan, M. ^{[1
]}

Meyer, M. D. ^{[1
]}

机构：

[1] Abbott Labs, Neurosci Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2008年 / 153卷 / 05期

关键词：

nicotinic acetylcholine receptor; alpha 7 nicotinic receptor; Xenopus oocytes; cognition; tilorone;

D O I：

10.1038/sj.bjp.0707649

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background and purpose: The alpha 7 nicotinic acetylcholine receptor ( nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha 7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha 7-selective agonist and characterizes analogues developed from this lead. Experimental approach: Activity and selectivity were determined from rat brain alpha 7 and alpha 4 beta 2 nAChR binding, recombinant nAChR activation, and native alpha 7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. Key results: Tilorone bound alpha 7 nAChR (IC50 110 nM) with high selectivity relative to alpha 4 beta 2 ( IC50 70 000 nM), activated human alpha 7 nAChR with an EC50 value of 2.5 mu M and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha 3 beta 4 or alpha 4 beta 2 nAChRs. However, the rat alpha 7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one(A-844606) with improved binding (alpha 7 IC50 11 nM, alpha 4 beta 2 IC50 > 30000 nM) and activity at both human and rat alpha 7 nAChR (EC(50)s 1.4 and 2.2 mu M and apparent efficacies 61 and 63%, respectively). These compounds also activated native alpha 7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. Conclusions and implications: Tilorone, known as an interferon inducer, is a selective alpha 7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of alpha 7 nAChR selective agonists. Whether alpha 7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of alpha 7 nAChR agonists remains to be elucidated.

引用

页码：1054 / 1061

页数：8

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