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, Dianne, Alewood, Paul F., and Lewis, Richard J. (2009) chi-Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. Journal of Medicinal Chemistry, 52 (22). pp. 6991-7002.

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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.

Item ID:	39026
Item Type:	Article (Research - C1)
ISSN:	1520-4804
Funders:	AusIndustry, National Health and Medical Research Council of Australia (NHMRC)
Date Deposited:	04 Jun 2015 03:53
FoR Codes:	03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030406 Proteins and Peptides @ 100%
SEO Codes:	97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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