title: Nobilamides A-H, long-acting transient receptor potential vanilloid-1 (TRPV1) antagonists from mollusk-associated bacteria.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Utah , Salt Lake City, UT 84112, USA.
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Lin
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
authors.forename: Rowena
authors.initials: R
authors.lastname: Antemano
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Hughen
authors.forename: Lenny
authors.initials: L
authors.lastname: Marett
authors.forename: Gisela P
authors.initials: GP
authors.lastname: Concepcion
authors.forename: Margo G
authors.initials: MG
authors.lastname: Haygood
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
authors.forename: Alan
authors.initials: A
authors.lastname: Light
authors.forename: Eric W
authors.initials: EW
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049851:Gastropoda / Q000382:microbiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011485:Protein Binding; D013302:Streptomyces / Q000737:chemistry*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D047630:Depsipeptides; D009842:Oligopeptides; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin; D002118:Calcium