χ-Conopeptide Pharmacophore Development: Toward a Novel Class of Norepinephrine Transporter Inhibitor (Xen2174) for Pain

• Published in: Journal of medicinal chemistry Vol. 52; no. 22; pp. 6991 - 7002
• Main Authors: 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, Lewis, Richard J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.11.2009; Amer Chemical Soc
• Subjects: Allosteric Regulation; Amino Acid Sequence; Analgesics; Animals; Biological and medical sciences; Catecholaminergic system; Cercopithecus aethiops; Chemistry, Medicinal; Conotoxins - chemistry; COS Cells; Drug Discovery; Drug Stability; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine Plasma Membrane Transport Proteins - antagonists & inhibitors; Norepinephrine Plasma Membrane Transport Proteins - chemistry; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Pain - drug therapy; Pain - metabolism; Peptides - adverse effects; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Structure-Activity Relationship; NEUROPATHIC PAIN; PROTEIN STRUCTURES; SPECTROSCOPY; AMINO-ACIDS; NMR STRUCTURE CALCULATION; NUCLEAR-MAGNETIC-RESONANCE; SPIN COUPLING-CONSTANTS; TORSION ANGLE DYNAMICS; NORADRENALINE; PEPTIDE; Human; Peptides; Rat; Rodentia; Catecholamine; In vitro; In vivo; Vertebrata; Mammalia; Analgesic; Structure activity relation; Membrane transport; Animal; Biogenic amine; Neurotransmitter; Non competitive inhibition; Inhibitor; Norepinephrine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9003413

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.