Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Calcium / metabolism
-
Capsaicin / antagonists & inhibitors
-
Cells, Cultured
-
Depsipeptides / chemical synthesis*
-
Depsipeptides / chemistry
-
Depsipeptides / isolation & purification
-
Depsipeptides / pharmacology*
-
Ganglia, Spinal / cytology
-
Ganglia, Spinal / drug effects*
-
Ganglia, Spinal / metabolism
-
Gastropoda / microbiology
-
HEK293 Cells
-
Humans
-
Mice
-
Molecular Structure
-
Oligopeptides / chemical synthesis*
-
Oligopeptides / chemistry
-
Oligopeptides / isolation & purification
-
Oligopeptides / pharmacology*
-
Protein Binding
-
Streptomyces / chemistry*
-
Structure-Activity Relationship
-
TRPV Cation Channels / antagonists & inhibitors*
-
Time Factors
Substances
-
Depsipeptides
-
Oligopeptides
-
TRPV Cation Channels
-
TRPV1 receptor
-
Capsaicin
-
Calcium