χ-Conopeptide Pharmacophore Development: Toward a Novel Class of Norepinephrine Transporter Inhibitor (Xen2174) for Pain

被引：68

作者：

Brust, Andreas ^{[1
]}

Palant, Elka ^{[1
]}

Croker, Daniel E. ^{[1
]}

Colless, Barbara ^{[1
]}

Drinkwater, Roger ^{[1
]}

Patterson, Brad ^{[1
]}

Schroeder, Christina I. ^{[2
]}

Wilson, David ^{[1
]}

Nielsen, Carsten K. ^{[3
]}

Smith, Maree T. ^{[3
]}

Alewood, Dianne ^{[1
]}

Alewood, Paul F. ^{[2
]}

Lewis, Richard J. ^{[1
,2
]}

机构：

[1] Xenome Ltd, Indooroopilly, Qld 4068, Australia

[2] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[3] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 22期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

NMR STRUCTURE CALCULATION; NUCLEAR-MAGNETIC-RESONANCE; SPIN COUPLING-CONSTANTS; TORSION ANGLE DYNAMICS; PROTEIN STRUCTURES; NEUROPATHIC PAIN; AMINO-ACIDS; SPECTROSCOPY; PEPTIDE; NORADRENALINE;

D O I：

10.1021/jm9003413

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. chi-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models or neuropathic pain. An analogue of chi-MrIA has been found to be a suitable drug candidate. On the basis of the NMR solution structure of this related peptide, Xen2174 (3), and structure-activity relationships of analogues, a pharmacophore model for the allosteric binding of 3 to NET is proposed. It is shown that 3 interacts with NET predominantly through amino acids in the First loop, forming a tight inverse turn presenting amino acids Tyr7, Lys8, and Leu9 in an orientation allowing for high affinity interaction with NET. The second loop interacts with a large hydrophobic pocket within the transporter. Analogues based on the pharmacophore demonstrated activities that support the proposed model. On the basis of improved chemical stability and a wide therapeutic index, 3 was selected for further development and is currently in phase II clinical trials.

引用

页码：6991 / 7002

页数：12

共 56 条

[1] Drugs From the Sea: Conotoxins as Drug Leads for Neuropathic Pain and Other Neurological Conditions [J].