TY - JOUR
T1 - Nobilamides A-H, long-acting transient receptor potential vanilloid-1 (TRPV1) antagonists from mollusk-associated bacteria
AU - Lin, Zhenjian
AU - Reilly, Christopher A.
AU - Antemano, Rowena
AU - Hughen, Ronald W.
AU - Marett, Lenny
AU - Concepcion, Gisela P.
AU - Haygood, Margo G.
AU - Olivera, Baldomero M.
AU - Light, Alan
AU - Schmidt, Eric W.
PY - 2011/6/9
Y1 - 2011/6/9
N2 - New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain.
AB - New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain.
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U2 - 10.1021/jm101621u
DO - 10.1021/jm101621u
M3 - Article
C2 - 21524089
AN - SCOPUS:79958106628
SN - 0022-2623
VL - 54
SP - 3746
EP - 3755
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -