title: A new metabotropic glutamate receptor agonist with in vivo anti-allodynic activity.
abstract: As part of the vital search towards improved therapeutic agents for the treatment of neuropathic pain, the central nervous system glutamate receptors have become a major focus of research. Outlined herein are the syntheses of two new biologically active 3'-cycloalkyl-substituted carboxycyclopropylglycines, utilizing novel synthetic chemistry. The reaction between substituted 1,2-dioxines and an aminophosphonate furnished the cyclopropane core in a single step with all required stereochemistry of pendant groups. In vitro binding assays at metabotropic glutamate receptors revealed selective activity. In vivo testing in a rodent model of neuropathic pain indicated one amino acid significantly and dose-dependently decreased mechanical allodynia.
authors.affiliation: Discipline of Chemistry, The University of Adelaide, Adelaide, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Stanley
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Trine
authors.initials: T
authors.lastname: Kvist
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jesper Mosolff
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Avery
authors.forename: Edward R T
authors.initials: ER
authors.lastname: Tiekink
authors.forename: Daniel Sejer
authors.initials: DS
authors.lastname: Pedersen
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Irvine
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Taylor
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism
chemical_list: D000700:Analgesics; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; D005998:Glycine