chi-Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain.
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.
Xenome Ltd., 120 Meiers Road, Indooroopilly, Queensland, Australia 4068. andreas.brust@xenome.com
Andreas
A
Brust
Elka
E
Palant
Daniel E
DE
Croker
Barbara
B
Colless
Roger
R
Drinkwater
Brad
B
Patterson
Christina I
CI
Schroeder
David
D
Wilson
Carsten K
CK
Nielsen
Maree T
MT
Smith
Dianne
D
Alewood
Paul F
PF
Alewood
Richard J
RJ
Lewis
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D020916:Conotoxins / Q000737:chemistry*; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D020916:Conotoxins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010455:Peptides; C500187:Xen2174; C507563:chi-conopeptide MrIA, Conus