A new metabotropic glutamate receptor agonist with in vivo anti-allodynic activity.
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.
Stanley
Nathan J
NJ
Discipline of Chemistry, The University of Adelaide, Adelaide, Australia.
Hutchinson
Mark R
MR
Kvist
Trine
T
Nielsen
Birgitte
B
Mathiesen
Jesper Mosolff
JM
Bräuner-Osborne
Hans
H
Avery
Thomas D
TD
Tiekink
Edward R T
ER
Pedersen
Daniel Sejer
DS
Irvine
Rodney J
RJ
Abell
Andrew D
AD
Taylor
Dennis K
DK
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
D000700:Analgesics; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; D005998:Glycine