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CHARACTERIZATION OF SYNTHETIC IRCINIANIN ANALOGUES AS POTENT AND SELECTIVE MODULATORS OF α3 GLYCINE RECEPTOR
Author(s) -
Talwar Sahil,
Xiao Xue,
Zhang Yan,
Vaughan Christopher,
Capon Robert,
Lynch Joseph
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.770.6
Subject(s) - glycine receptor , chemistry , glycine , pharmacology , hyperalgesia , receptor , patch clamp , ion channel , inhibitory postsynaptic potential , hek 293 cells , biophysics , stereochemistry , biochemistry , amino acid , nociception , medicine , biology
Glycine receptor (GlyR) chloride channel is a member of the pentameric Cys‐loop ligand‐gated ion channel family that mediates inhibitory neurotransmission. Probes that specifically enhance α3‐containing GlyRs have emerged as potential treatment for inflammatory pain. Previously, we reported that variabilin analogues (sponge Ircinia variabilis ) might be useful for selective GlyR drug development. Hence, the aim was to characterize novel synthetic variabilin analogues. 107 compounds were subjected to automated patch clamp screening using HEK293 cells expressing α1 and α3 GlyRs. E11 potentiated (EC 20 glycine) α1 GlyR at lower doses but inhibited at higher doses (>30 μM). Whereas, B10 (EC 50 ~0.3μM) potentiated current of both receptors but had a stronger effect on α3. Intrathecal administration of B10 in rats showed moderate increase in maximum possible effect (MPE) (Complete Freud's adjuvant induced thermal hyperalgesia) with mild motor side effects in rotarod apparatus. Based on B10 , 18 analogues were designed to achieve high α3>α1 selectivity and were subjected to screening. Out of 18, H01 was found to be highly α3 selective with 184 ± 12 % potentiation of EC 20 glycine current (α1= 91 ± 24 %). Further, intrathecal administration of H01 (100 nM) in rats showed dose dependent increase in %MPE in inflammation‐induced allodynia with less motor activity disruption. H01 prolonged glycine current decay time for α3 in comparison to α1 GlyRs in artificial synapses.