title: Constrained TRPV1 agonists synthesized via silver-mediated intramolecular azo-methine ylide cycloaddition of α-iminoamides.
abstract: As part of an effort to identify agonists of TRPV1, a peripheral sensory nerve ion channel, high throughput screening of the NIH Small Molecule Repository (SMR) collection identified MLS002174161, a pentacyclic benzodiazepine. A synthesis effort was initiated that ultimately afforded racemic seco analogs 12 of the SMR compound via a silver mediated intramolecular [3+2] cycloaddition of an azo-methine ylide generated from α-iminoamides 11. The cycloaddition set four contiguous stereocenters and, in some cases, also spontaneously afforded imides 13 from 12. The synthesis of compounds 12, the features that facilitated the conversion of 12-13, and their partial agonist activity against TRPV1 are discussed.
authors.affiliation: Center for Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, KS 66047, United States.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Painter
authors.affiliation: Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Building 10, Room 2C401, 10 Center Drive, MSC 1510, Bethesda, MD 20892-1510, United States.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Kaszas
authors.affiliation: Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Building 10, Room 2C401, 10 Center Drive, MSC 1510, Bethesda, MD 20892-1510, United States.
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Gross
authors.affiliation: The University of Kansas Molecular Structures Group, 1251 Wescoe Hall Drive, Lawrence, KS 66045, United States.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Douglas
authors.affiliation: The University of Kansas Molecular Structures Group, 1251 Wescoe Hall Drive, Lawrence, KS 66045, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Day
authors.affiliation: Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Building 10, Room 2C401, 10 Center Drive, MSC 1510, Bethesda, MD 20892-1510, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
authors.affiliation: Center for Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, KS 66047, United States. Electronic address: nyprphd@yahoo.com.
authors.forename: Conrad
authors.initials: C
authors.lastname: Santini
mesh_terms: D000577:Amides / Q000737:chemistry*; D001391:Azo Compounds / Q000737:chemistry*; D001570:Benzodiazepinones / Q000737:chemistry*; D002211:Capsaicin / Q000737:chemistry; D003500:Cyclization; D061565:Cycloaddition Reaction; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D007097:Imines / Q000737:chemistry*; D012834:Silver / Q000737:chemistry*; D050916:TRPV Cation Channels / Q000819:agonists*
chemical_list: D000577:Amides; D001391:Azo Compounds; D001570:Benzodiazepinones; D006576:Heterocyclic Compounds, 4 or More Rings; D007097:Imines; C000592756:MLS002174161; D050916:TRPV Cation Channels; D012834:Silver; D002211:Capsaicin
keywords: Chronic pain; Intramolecular cycloaddition; Peripheral nerve ion channels; TRPV1 agonists