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.
|
Authors | Andreas Brust, Elka Palant, Daniel E Croker, Barbara Colless, Roger Drinkwater, Brad Patterson, Christina I Schroeder, David Wilson, Carsten K Nielsen, Maree T Smith, Dianne Alewood, Paul F Alewood, Richard J Lewis |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 22
Pg. 6991-7002
(Nov 26 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19860431
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Conotoxins
- Norepinephrine Plasma Membrane Transport Proteins
- Peptides
- Xen2174
- chi-conopeptide MrIA, Conus
|
Topics |
- Allosteric Regulation
- Amino Acid Sequence
- Animals
- COS Cells
- Chlorocebus aethiops
- Conotoxins
(chemistry)
- Drug Discovery
- Drug Stability
- Humans
- Hydrogen Bonding
- Inhibitory Concentration 50
- Magnetic Resonance Spectroscopy
- Models, Molecular
- Molecular Conformation
- Norepinephrine Plasma Membrane Transport Proteins
(antagonists & inhibitors, chemistry, metabolism)
- Pain
(drug therapy, metabolism)
- Peptides
(adverse effects, chemistry, metabolism, pharmacology)
- Rats
- Structure-Activity Relationship
|