X-conopeptide pharmacophore development: Toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain

Brust, Andreas, Palant, Elka, Croker, Daniel E., Colless, Barbara, Drinkwater, Roger, Patterson, Brad, Schroeder, Christina I., Wilson, David, Nielsen, Carsten K., Smith, Maree T., Alewood, Danne, Alewood, Paul F and Lewis, Richard J. (2009) X-conopeptide pharmacophore development: Toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. Journal of Medicinal Chemistry, 52 22: 6991-7002.


Author Brust, Andreas
Palant, Elka
Croker, Daniel E.
Colless, Barbara
Drinkwater, Roger
Patterson, Brad
Schroeder, Christina I.
Wilson, David
Nielsen, Carsten K.
Smith, Maree T.
Alewood, Danne
Alewood, Paul F
Lewis, Richard J.
Title X-conopeptide pharmacophore development: Toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain
Formatted title x-Conopeptide pharmacophore development: Toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2009-10
Year available 2009
Sub-type Article (original research)
DOI 10.1021/jm9003413
Volume 52
Issue 22
Start page 6991
End page 7002
Total pages 12
Place of publication Washington, DC, U. S. A.
Publisher American Chemical Society
Collection year 2010
Language eng
Subject C1
97 Expanding Knowledge
970106 Expanding Knowledge in the Biological Sciences
03 Chemical Sciences
0304 Medicinal and Biomolecular Chemistry
Abstract 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 of 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.
Formatted abstract Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. χ-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models of neuropathic pain. An analogue of χ-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.
Keyword Nmr Structure Calculation
Nuclear-magnetic-resonance
Spin Coupling-constants
Torsion Angle Dynamics
Protein Structures
Neuropathic Pain
Amino-acids
Spectroscopy
Peptide
Noradrenaline
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Sun, 29 Nov 2009, 00:02:56 EST