χ-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. 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 3to NET is proposed. It is shown that 3interacts 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, 3was selected for further development and is currently in phase II clinical trials. [ABSTRACT FROM AUTHOR]